Regulatory Safety Assessment of Nanomaterials701594/FULLTEXT01.pdfBreak-out groups on test guidelines and their applicability to assess NMs..... 45 4.1 Existing test guidelines and

Regulatory Safety Assessment of NanomaterialsAre we facing the same challenges as the regulation of endocrine disrupting chemicals?

Ved Stranden 18DK-1061 København Kwww.norden.org

The Nordic NanoNet Workshop and EDC discussion was organised in October 2011 in Espoo, Finland as part of the 2011 Finnish chairmanship of the Nordic Council of Ministers (NMR). The workshop focused on the safety assessment and management of nanomaterials (NMs) while reflecting on experiences in regulating endocrine disrupting chemicals (EDCs). This report describes the presentations, break-out group discussions and conclusions of the meeting. The regulatory frameworks and links between NMs and EDCs as well as the applicability of test guidelines and risk assessment tools for nanomaterials were addressed in presen-tations and break-out group work. Regulatory possibilities were further considered in a panel-led discussion. The Nordic dimen-sion was of special interest: strengthening of Nordic regulatory cooperation in the field of nanosafety gained support, while com-mencing a TG/GD project in the OECD test guideline programme was seen a concrete idea for future cooperation.

Regulatory Safety Assessment of Nanomaterials

TemaN

ord 2012:515

TemaNord 2012:515ISBN978-92-893-2343-7http://dx.doi.org/10.6027/TN2012-515

conference proceeding

TN2012515 omslag.indd 1 15-06-2012 09:59:32

Regulatory Safety Assessment of

Nanomaterials

Are we facing the same challenges as the regulation of endocrine disrupting chemicals?

Jukka Ahtiainen & Elina Väänänen,

Finnish Safety and Chemicals Agency (Tukes)

TemaNord 2012:515

Regulatory Safety Assessment of Nanomaterials Are we facing the same challenges as the regulation of endocrine disrupting chemicals?

Jukka Ahtiainen & Elina Väänänen, Finnish Safety and Chemicals Agency (Tukes)

TemaNord 2012:515 ISBN 978-92-893-2343-7

http://dx.doi.org/10.6027/TN2012-515

© Nordic Council of Ministers 2012

Cover photo: Image Select

This publication has been published with financial support by the Nordic Council of Ministers.

However, the contents of this publication do not necessarily reflect the views, policies or recom-mendations of the Nordic Council of Ministers.

www.norden.org/en/publications

Nordic co-operation

Nordic co-operation is one of the world’s most extensive forms of regional collaboration, involv-ing Denmark, Finland, Iceland, Norway, Sweden, and the Faroe Islands, Greenland, and Åland.

Nordic co-operation has firm traditions in politics, the economy, and culture. It plays an im-

portant role in European and international collaboration, and aims at creating a strong Nordic community in a strong Europe.

Nordic co-operation seeks to safeguard Nordic and regional interests and principles in the

global community. Common Nordic values help the region solidify its position as one of the world’s most innovative and competitive.

Nordic Council of Ministers Ved Stranden 18

DK-1061 Copenhagen K

Phone (+45) 3396 0200

www.norden.org

http://dx.doi.org/10.6027/TN2012-515

http://www.norden.org/en/publications

http://www.norden.org

Content

Preface........................................................................................................................................................ 7

Summary and Conclusions.................................................................................................................. 9

1. Introductory presentations ...................................................................................................... 17 1.1 Technical challenges and policy issues (Jukka Ahtiainen, Tukes, FI) .......... 17 1.2 Networks as a tool for regulatory actions: The Danish Endocrine

Network (Henrik Tyle, Danish EPA, DK) ................................................................ 18 1.3 The OECD Conceptual Framework on Endocrine Disrupters

(Petteri Talasniemi, Tukes, FI) .................................................................................. 20 1.4 Revised OECD Conceptual Framework for Endocrine Disrupters and

the draft OECD GD on testing and assessment of chemicals for ED (Henrik Tyle, Danish EPA, DK)...................................................................................... 21

1.5 NM definition and substance identification (Emma Vikstad, Kemi, SE) ............ 23 1.6 Implementing REACH on NMs: EU guidance on NM safety

assessment (Poul Bo Larsen, Danish EPA, DK) .................................................... 24

2. Break-out groups on the regulatory framework and the links between EDC and NM issues ...................................................................................................................... 27 2.1 Decisions and guidance – proceed or wait for new scientific

information? ..................................................................................................................... 27 2.2 Definining EDCs and NMs ............................................................................................ 29 2.3 REACH – regulating EDCs and NMs.......................................................................... 31 2.4 Registration of NMs ....................................................................................................... 33 2.5 Adequacy of existing legislation to regulate confirmed EDCs ........................ 34 2.6 A practical example on NMs REACH registration of Nano Fibril

Cellulose ............................................................................................................................. 34

3. Presentations on test guidelines and their applicability to assess NMs .................. 35 3.1 What TG tools we have, and which TGs and GDs have to be

developed for NM testing (Peter Kearns, OECD EHS/ENV) ............................ 35 3.2 REACH and Information Requirements for safety assessment

(Jukka Ahtiainen, Tukes, FI) ....................................................................................... 36 3.3 OECD Sponsorship Programme and NM testing (Sjur Andersen,

KLIF, NO) ........................................................................................................................... 37 3.4 Nordic nanoAg contribution to the Sponsorship Programme

(Janneck Scott-Fordsmand, DMU, DK) ...................................................................... 38 3.5 Environmental fate studies on NMs (Erik Joner, Bioforsk, NO and

Deborah Oughton, Norwegian University of Life Sciences, NO) .................... 39 3.6 Detection of NMs in the environment and verification of exposure

(Geert Cornelis, University of Gothenburg, SE) ................................................... 40 3.7 Inhalation of nanoparticles and health effects (Marit Låg,

Norwegian Institute of Public Health, NO) ........................................................ 41 3.8 Update on genotoxicity of NMs (Julia Catalán, FIOH, FI) .................................. 42 3.9 In vitro studies in NM testing - Experience from NanoTEST (Lise

Fjellsbø, NILU, NO) ......................................................................................................... 42 3.10 Aquatic effects and fate of nanomaterials in the Nordic

environment (Jussi Kukkonen, University of Eastern Finland, FI) ............... 43

4. Break-out groups on test guidelines and their applicability to assess NMs ........... 45 4.1 Existing test guidelines and new guidance for the hazard and safety

assessment of NMs ......................................................................................................... 45 4.2 Technical guidance for specific areas of testing .................................................. 47 4.3 Guidance based on NM groups .................................................................................. 47 4.4 Nanospecific endpoints ................................................................................................ 48 4.5 Test Guideline Modification and the Mutual Acceptance of Data ................. 49

5. Presentations on the regulatory possibilities for EDCs and NMs............................... 51 5.1 Outcome of the three Nordic workshops on EDCs held in Denmark

in 2010 (Sofie Christiansen, DTU, Pia Juul Nielsen and Rikke Holmberg, Danish EPA, DK) ........................................................................................ 51

5.2 Regulation of combined effects – status of the EU work (Rikke Holmberg, Danish EPA, DK) ........................................................................................ 52

5.3 Registration of ZnO in REACH – is it sufficient for safety evaluation of nano ZnO? (Katarzyna Malkiewicz, Kemi, SE) ................................................ 52

6. Presentations on regulating NMs........................................................................................... 57 6.1 Summary on the TG applicability and TG/GD needs (Poul Bo

Larsen, Danish EPA, DK and Jukka Ahtiainen, Tukes, FI)................................. 57 6.2 Current regulatory views in the EU (Henrik Laursen, DG ENV, EC) ............ 58 6.3 Registrations of NMs (Marita Luotamo, ECHA) ................................................... 59 6.4 Towards harmonization of national databases for NMs on the market

(Juan Pineros, MoE, BE) .................................................................................................. 60 6.5 French reporting scheme for Nanomaterials (Clarisse Durand, Ministry

of Ecology, Sustainable Development, Transports and Housing, FR) ................ 61 6.6 Example(s) on NM safety assessment and RMM (Nicole Palmen,

RIVM, NL) .......................................................................................................................... 62 6.7 Nanotoxicology: Science at the interphases, Estonian perspective (Kaja

Kasemets, National Institute of Chemical Physics and Biophysics, EE)............. 63

7. Discussion and views on Nordic possibilities in regulating NMs ............................... 65 7.1 The OECD Sponsorship Programme and its progress ....................................... 65 7.2 TG and GD development .............................................................................................. 66 7.3 REACH implementation ............................................................................................... 66 7.4 NM product labelling and registers ......................................................................... 68 7.5 Establishing a Nordic Regulatory NM network ................................................... 68

Sammanfattning och slutsatser ..................................................................................................... 69

Abbreviations ....................................................................................................................................... 77

Appendix A: Programme .................................................................................................................. 79

Appendix B: Presentations .............................................................................................................. 83

Appendix C: List of Participants..................................................................................................... 85

Preface

Opening Speech

“Ladies and gentlemen,

I would like to wish you a warm welcome to Finland and to Hanasaari

Congress Centre. I am very pleased to have this opportunity to address

this meeting. Nordic cooperation is much appreciated here in Finland,

and I know that the cooperation on chemical issues has contributed a lot

to our work towards better management of hazardous substances on the

EU level and internationally.

The Nordic governmental cooperation within the field of chemicals

began already in 1976 with the establishment of the Nordic Product

Control Group. In comparison, the Nordic Council of Ministers was es-

tablished in 1971. At that time, only Denmark was a member of the Eu-

ropean Community. This meant that most of the discussions in the Nor-

dic Product Control Group focused on issues brought to and discussed in

the context of the European Community chemicals agenda. Many criteria

documents for harmonized classification of chemical substances were

prepared within the Control Group and, then, were taken to the EU by

our Danish colleagues. Ten years after the group was formed, the name

of the group was changed to the Nordic Chemicals Group.

One of the most successful Nordic cooperation efforts on chemicals,

which I would like to mention, was carried out in 1987–1992 on the

strengthening of global discussions concerning ozone depleting substances.

In 1995 Finland and Sweden joined the European Community. This

triggered the need for an overall review of the aims and organizational

structure of the Nordic governmental cooperation within the framework

of the Nordic Council of Ministers. The cooperation thus became more

focused and, according to political aims, should be carried out within are-

as where there is an added Nordic value (nordiskt nytta), that is, where

there is a need to cooperate because it strengthens the corresponding

national, European or global work.

The cooperation within the Nordic Chemicals Group has always been

seen as close and successful. It has been commended during all reviews,

8 Regulatory Safety Assessment of Nanomaterials

especially because of its ability to change focus according to the needs of

the work. I am supporting this assessment, based on my own experienc-

es of serving for 15 years as the Finnish representative on the Nordic

committee for environmental issues.

The Chemicals Group has worked in areas where the Nordic coun-

tries share equal aims concerning health and environmental protection.

Many thanks to the committed people working on these projects.

The present Finnish Government has also expressed support of the

Nordic work on chemical issues in general and on related issues under

discussion in this very seminar. This is what the Government Pro-

gramme says:

“Implementation of the (2006 launched) National Chemicals Programme will

continue. The adequacy of the current measures in achieving the internation-

al goals regarding the minimisation of the environmental and health risks of

chemicals by 2020 will be assessed and the programme revised accordingly.

The need for additional measures required by new and upcoming subjects

such as nano materials, materials affecting hormonal activity, and the interac-

tion of chemicals will be evaluated.”

By arranging this seminar, the Nordic Nano Steering group, the Nordic

Risk Assessment Group, Nord-UTTE on test guideline work and the Nor-

dic Council of Ministers are giving their valuable input also into the im-

plementation of our Government Programme. But what is even more

important, as a part of Nordic efforts, is that this meeting is a step along

the way to developing criteria for EU- and international-level safety as-

sessments and risk management practices for nanos and EDCs.

I would like to encourage all of you to actively take part in exchanging

information and in discussions, not only during the sessions but also

informally in hallway chats, to take full advantage of the well-prepared

agenda and the top experts who are present here as speakers or partici-

pants. I hope you will have a successful meeting here in Hanasaari dur-

ing the upcoming three days.”

Pekka Jalkanen

Ministry of the Environment Finland and

Chair of the Nordic Committee of Senior Officials

for Environmental Affairs

Nordic Council of Ministers

Summary and Conclusions

The Nordic NanoNet Workshop and EDC discussion was organised as

part of the 2011 Finnish chairmanship of the Nordic Council of Ministers

(NMR). The conference, organised by the Finnish Safety and Chemicals

Agency (Tukes), took place between the 11th and 13th of October 2011 at

Hanasaari Congress Centre in Espoo, Finland. While the meeting focused

on the safety assessment and management of nanomaterials (NMs), a

parallel one-day session was dedicated to Endocrine Disrupting Chemi-

cals (EDC) Criteria. The organisers are thankful to the Nordic Council of

Ministers for providing the resources for the meeting.

The broad themes of the conference were:

The regulatory frameworks and the links between NMs and EDCs

Applicability of test guidelines and risk assessment tools for

nanomaterials

Regulatory possibilities for EDCs and NMs

Regulation of NMs

Developing EDC Criteria

Future Nordic regulatory cooperation

The Regulatory Framework and the Links between EDC and NM Issues

Introductory presentations on the regulatory framework and the links

between EDC and NM issues were launched by Jukka Ahtiainen (Tukes,

FI), who introduced some of the central themes and objectives of the

meeting. Speaking on behalf of Pia Juul Nielsen, Henrik Tyle (Danish

EPA, DK) used the Danish Endocrine Network as an example of a net-

work for regulatory action that has improved understanding between

regulators and scientists. Petteri Talasniemi (Tukes, FI) introduced the

revised OECD Conceptual Framework (CF) and pointed out that guid-

ance limitations stem from two sources: either there is insufficient expe-

rience of the use of the assay in question or the assay does not offer sig-

nificant advantages over existing studies. In his presentation on the re-

vised OECD CF and the draft OECD Guidance Document (GD) for EDCs,

Henrik Tyle advocated a case-by-case approach to chemicals assessment

that takes into account all available information.


Emma Vikstad (Kemi, SE) highlighted the imperative for a single na-

nomaterial definition to encompass all nanorelevant EU legislation. Poul

Bo Larsen (Danish EPA, DK) pointed out that much work is needed to

incorporate nanomaterials into REACH and suggested that perhaps a

separate, more flexible regulation for nanomaterials in parallel with

REACH could be an appropriate solution.

Break-out groups on the regulatory frameworks and the links be-

tween EDC and NM issues concluded the first day of the conference. The

conclusions are presented below.

Proceed with decisions or wait for more scientific information?

The view that we should not wait for more scientific information before

going forward with decisions and guidance prevailed. In the case of

nano, high uncertainty and lack of clarity on what further information is

needed strengthens the case for swift regulatory action. For EDCs, the

basis for regulation and the state of the knowledge is better-defined.

Defining nanomaterials

All groups saw an imminent need for a nanomaterials definition to allow

regulatory action to take place. A practical approach to the definition

was favoured in the current situation of persistent uncertainty. It was

however concluded that the scientific basis should be incorporated into

this practical approach. Groups also agreed on the need of an EDC defini-

tion and criteria covering all hormonal modalities.

REACH – regulating EDCs and NMs

Even though there was no consensus opinion on how the REACH regula-

tion could ensure the safety of NMs, participants agreed that further

measures to ensure safety under the regulation are needed. Potential

methods for ensuring that NMs are addressed separately from the bulk

substance include amending the regulation or providing new or revised

annexes or adequate ECHA guidance for registration. It was seen that for

the identification of EDCs under REACH, a new Annex on EDC criteria,

alike to the annex for PBT criteria, was probably necessary.

Registation of NMs

There was a strong general feeling, that it would be safer to categorically

register NMs as new substances with nano-adapted data requirements.

Nevertheless, other adequate means, such as better ECHA guidance on

registration, were also supported.

Regulatory Safety Assessment of Nanomaterials 11

Adequacy of existing legislation to regulate EDCs

The existing regulatory tools were considered generally adequate to

regulate confirmed EDCs. However, the combined effects of EDCs from

different sources were perceived difficult to address sufficiently by ex-

isting legislation.

Applicability of Test Guidelines and Risk Assessment Tools for Nanomaterials

The second day of the Nordic NanoNet Workshop focused on the ap-

plicability of test guidelines (TGs) and risk assessment (RA) tools for

nanomaterials. Peter Kearns’ (OECD, EHS/ENV) presentation gave an

overview of OECD work on NMs and elaborated on the relationship of

the principles of Good Laboratory Practice and the Mutual Acceptance of

Data in relation to test guideline and guidance document development.

Jukka Ahtiainen outlined possibilities for further development of testing

practice: the creation of a conceptual framework for NM testing and

assessment in the style of the EDC Conceptual Framework is an option.

Sjur Andersen (KLIF, NO) presented on the OECD sponsorship pro-

gramme and introduced the scope of testing and the relevant sponsors

involved. Janneck Scott-Fordsmand (DMU, DK) elaborated on the Nordic

nanosilver contributions to the sponsorship programme and discussed

some of its testing challenges, sparking a lively discussion.

Erik Joner (Bioforsk, NO) and Deborah Oughton (Norwegian Univer-

sity of Life Sciences, NO) jointly presented on environmental fate studies

on NMs: testing in relevant soil conditions including ageing was con-

cluded to be important as were the possibilities for using neutron action

as a method to detect metallic NMs. Geert Cornelis (University of

Gothenburg, SE) then addressed the detection of NMs in the environ-

ment and the issues relating to the verification of exposure – field-flow

fractionation (FFF) coupled to inductively coupled plasma-mass spec-

trometry (ICP-MS) and single particle ICP-MS (SP-ICP-MS) were pro-

posed for sensitive analysis of engineered nanoparticles in complex en-

vironmental media.

In her presentation on the inhalation of nanoparticles, Marit Låg

(Norwegian Institute of Public Health, NO) concluded that engineered

nanoparticles have a potential to elucidate health effects, the toxicity of

which will depend on the exposure to these particles. Julia Catalán (FI-

OH, FI) gave an update on the genotoxicity testing of NMs and the chal-

lenges faced – for example, it is often unknown how much of the nano-

material is taken up by cells and whether differences in intracellular


pathways could explain differences in genotoxicity. Lise Fjellsbø (NILU,

NO) drew on experiences from the NanoTEST project studying the up-

take and transport of nanoparticels through biological barriers in dis-

cussing in vitro studies in NM testing. The final presentation of the day

was delivered by Jussi Kukkonen (University of Eastern Finland, FI) who

spoke about the aquatic effects and fate of nanomaterials in the Nordic

Environment.

The discussion on applicability continued in break-out group discus-

sions, the results of which are presented below.

Existing test guidelines and new guidance

Groups agreed that while development of further guidelines is neces-

sary, existing guidelines are an adept starting point for the safety and

hazard assessment of nanomaterials. The existence of technical and con-

ceptual challenges to the existing guidelines was acknowledged. The

need for flexibility in guidance was emphasised by all groups.

Guidance for specific areas of testing and guidance based on NM

groups

Different guidance for different areas of testing was seen necessary.

Grouping nanomaterials remains practically difficult. Nevertheless, it

was seen that if grouping could overcome these practical hurdles, it

would be a desirable basis for guidance.

Regulatory possibilities for EDCs and NMs

The third day of the conference began with a session on the regulatory

possibilities for EDCs and NMs. Sofie Christiansen, Pia Juul Nielsen and

Rikke Holmberg (Danish EPA, DK) presented the outcomes of three Nor-

dic EDC workshops on criteria, combined effects and soft regulatory

measures held in Copenhagen in the autumn of 2010. Rikke Holmberg

also delivered an update on the status of EU regulatory work on EDCs,

combined effects and NMs. Katarzyna Malkiewicz (Kemi, SE) ended the

session with her presentation on the registration of zinc oxide in REACH

by recommending the request of further nanospecific data in connection

to REACH substance evaluation. A separate session on developing EDC

criteria, parallel to a session on regulating nanomaterials was then run

by representatives of the Danish EPA.


Regulating NMs

In opening the session on regulating nanomaterials, Poul Bo Larsen

(Danish EPA, DK) and Jukka Ahtiainen (Tukes, FI) emphasised the emer-

gence of new nano-specific endpoints and the need to develop guidance

and new test guidelines in the area of physico-chemical properties.

Henrik Laursen (DG ENV, EC) provided an overview of key EU actions

and views on the regulation of NMs; the ongoing legislative overview aims

to establish whether current legislation ensures safety and sustainability

as well as competitiveness and innovation. Marita Luotamo (ECHA) dis-

cussed NM experiences and future developments under REACH: a case-

by-case approach to the registration of nanomaterials was preferred.

Juan Piñeros (MoE, BE) introduced the case for harmonizing national

databases for NMs on the market: benefits include enabling data collec-

tion and exposure estimations, risk assessment and managent systems

and improvement of the legislative framework. Clarisse Durand (Minis-

try of Ecology, Sustainable Development, Transport and Housing, FR)

then went into more detail on the French mandatory reporting scheme

initiative, undertaken in cooperation with Belgium and Italy.

Nicole Palmen (RIVM, NL) presented examples of NM safety assess-

ment, particularly from the point of view of occupational exposure to

engineered nanoparticles. The final presentation by Kaja Kasemets

(NICPB, EE) discussed research on the ecotoxicology of synthetic nano-

particles at the NICPB.

Discussion on Nordic regulatory cooperation on NMs

A discussion on Nordic cooperation within the EU and OECD frame-

works ended the Nordic NanoNet Workshop. The conclusions of this

discussion aimed for regulators are presented below.

The OECD Sponsorship Programme and its progress

There are huge expectations on the OECD testing of 13 nanomaterials for

various endpoints. The data from the ongoing explorative phase 1 for

possible hazard identification is not yet completely available but we

should already commence planning for phase 2, where the data pro-

duced should be suitable for risk assessment. The phase 2 testing should

be guided by some kind of a testing strategy or Conceptual Framework

like for EDCs, developed based on the existing data.


TG and GD development

In general, the OECD guidelines are applicable for investigating the

health effects, ecotoxicity and environmental fate of nanomaterials with

the important proviso that additional consideration needs to be given to

the physicochemical characteristics of the material tested. In some cases,

there may be a need for further modification to the OECD guidelines.

Preparation of samples and dose administration are critical considera-

tions for the tests and therefore guidance has been developed on sample

preparation and dosimetry for the safety testing of nanomaterials. The

preliminary review of OECD-WPMN is consequently seen as a “living”

document, highlighting the feasibility of various approaches and allow-

ing for continuous updates, given the rapid developments in this area.

There was a consensus that very few potential new nanospecific end-

points need to be added to the Test Guidelines or developed as new Test

Guidelines. These new nanospecific needs are mainly in the area of phys-

ico-chemical characterization. However, some of the endpoints in exist-

ing Test Guidelines are more nanorelevant than others. In the area of

ecotoxicity most of the existing endpoints are also nanorelevant. In the

area of environmental fate testing the detection and characterization of

NMs in the environmental media or in tissues is the challenge.

REACH implementation

The information submitted in the registration dossier for a nanomateri-

al, as part of the bulk registration or on its own, needs to comply with

the information requirements and, if relevant, the CSR requirements for

all the registrant’s identified uses of the nanomaterial.

There is no one-size-fits-all solution to treating nanomaterials as

forms of a bulk substance or a separate substance. Further practice

needs to evolve on developing rules on how size should be used as a

characterizer and when could it be used as an identifier. The Nordic

countries may have differing views on whether NMs should be always reg-

istered as substances of their own and considered as new substances. How-

ever, if the former were to apply, the data requirements based on tonnages

should be reconsidered.

If specific substance identification rules for nanomaterials are devel-

oped, they must be consistent with practices for substances in general.

Such rules need to maintain a certain degree of flexibility to allow use of

the most practical solutions, provided that the information is relevant

and complete for all forms of the substance, and that safe use is ensured.

REACH obliges the registrant to ensure that his registration(s) demon-

strate(s) that all forms of the substance in his dossier(s) can be used safe-

ly. The question of substance identity is not critical in this regard. The


focus of attention should therefore be on ensuring that the submitted data

are applicable or appropriate for the all form(s) covered in a dossier(s) in

question and on ensuring that the registrant has provided all relevant

information to allow the safe use of the substance by the downstream

users and consumers. There are however concerns amongst the Nordic

countries whether industry would comply with this properly. Only 3 regis-

trants out of 46 with NM use of the same substance had indicated the nano-

material use in IUCLID at the first registration in 2010.

Standard information requirements, as described in the Annexes VII –

XI, apply equally to nanoforms and bulkforms. The registrant has to make

sure that in case tests are performed, these must be representative of the

form(s) of the registered substance. It was concluded that nano-specific

data requirements would need new tonnage triggers and data require-

ments. This would also translate to the need for a common registration.

ECHA has been invited to further assess the relevant submitted dos-

siers in a “bottom-up” process to build up more knowledge and experi-

ence on substance identification in the registration of nanomaterials. If

appropriate, ECHA should use this experience to develop further practi-

cal rules in co-operation with the European Commission, Member States

and stakeholders. Such a bottom-up process should significantly con-

tribute to a better understanding on how nanomaterials are to be treat-

ed within the REACH framework. This could be perhaps supported by

Nordic countries as an interim solution. However, the revised ECHA Guid-

ance on registration should make explicit, that the registrants and SIEF

are to address and assess all the relevant uses of NMs of that particular

substance. This demand should be very visible and clear, probably under

the title “What to register”.

It was also proposed that if a member state’s regulators have doubts

that the safety assessment of a NM form is not adequate, these substances

(e.g. the case of ZnO; having the nanoform in the market) could be raised

into the CORAP (Community Rolling Action Plan for the evaluation of sub-

stances) process by a member state.

It was also discussed whether a separate regulation for nanomaterials

would be more appropriate, in order not to make changes within REACH.

Based on the experiences in the RIP-oNs and the experiences from the

OECD sponsorship programme, a future task for Nordic cooperation could

be to start work on examining specific triggers for data requirement and a

testing strategy for nanomaterials.


Establishing a Nordic Regulatory NM network

Strengthening Nordic cooperation in the field of nanosafety was support-

ed. This should bring together research groups and regulators. Regulatory

views could thus be better discussed and coordinated. The core of this

nano-group should also coordinate NM related work in all NKG groups.

If Nordic countries have reason to doubt the adequacy of NM safety

assessment in registration and one of the countries would take this to

the CORAP-process for substance evaluation, there should be strong

Nordic support and resources for this process.

Starting a TG/GD project in the OECD test guideline programme was

discussed as a concrete idea for future regulatory cooperation. The

meeting identified two possible fields where there is need for work and

Nordic scientific capacity. For ecotoxicology, the development of Guid-

ance Document(s) for soil and sediment toxicity could be such an area.

In the human health area, the knowledge on genotoxicity assessment

could be clearly identified. One possibility is to get involved with the

development of a Comet assay for an OECD TG, and ensure that it would

also become applicable for NM testing as well as for general chemicals.

1. Introductory presentations

1.1 Technical challenges and policy issues (Jukka Ahtiainen, Tukes, FI)

The introductory presentation on technical challenges and policy issues

related to EDCs and NMs raised some of the questions central to the

themes and goals of the meeting. A main concern was whether we

should proceed with decision-making and guidance on NMs and EDCs or

alternatively wait for new scientific information before acting. The ade-

quacy of the definitions for EDCs and NMs were addressed at length.

Should definitions be strictly scientific or also include practical consid-

erations? Should the EDC definition cover all hormonal modalities, in-

cluding effects related to immunotoxicology and metabolia? Should we

strive for a common NM definition in all EU legislation?

The adequacy of the current regulatory framework was also ad-

dressed. The role of REACH in regulating EDCs and NMs was highlighted,

especially with reference to potential revisions. Should only guidance for

registration and safety assessment be revised and updated? Should new

annexes in REACH be created for EDC criteria? Should a revised annex VI

identify NMs as their own and separate new substance with size and

form included as additional identifiers? Should NMs be generally regis-

tered as new substances, separate from the bulk substance or should the

registrant be allowed the discretion to determine how to handle them? If

a substance can be considered as a confirmed EDC, are regulatory ac-

tions in the new Biocide, PPP and REACH regulations sufficient?

A practical NM example on the REACH registration of Nano Fibril Cel-

lulose invited participants to consider three scenarios and their impact

on registration. Bearing in mind that bleached pulp is exempted from

registration, what should happen if nano fibril cellulose was manufac-

tured mechanically from cellulose pulp? What if it was coated by absorp-

tion (e.g. by polyvinyl acrylate)? How about if nano fibril cellulose was

chemically modified, would it then fall under the REACH registration?

Test guidelines and their applicability to assess NMs were also dis-

cussed from the point of view of existing guidelines and their develop-

ment. Can the hazard and safety assessment be managed by existing test

guidelines by only developing new technical guidance (e.g. OECD Guid-


ance Documents) applicable for the handling and characterisation of

exposures to NMs? Should this technical guidance be developed for vari-

ous areas of testing (e.g. soil studies, aquatic studies, or inhalation and

skin studies)? Should guidance be based on NM groups (e.g. metal, metal

oxide NMs)? The existence of new nano-specific or nano-relevant end-

points was raised including the areas of physical-chemical properties,

ecotoxicology environmental fate (degradation and accumulation in-

cluded) and toxicology.

The presentation did not seek to answer these multifaceted questions

but instead to set the backdrop for the meeting and invite participants to

engage with these questions in the course of the workshop, especially

during the break-out group work.

1.2 Networks as a tool for regulatory actions: The Danish Endocrine Network (Henrik Tyle, Danish EPA, DK)

Cooperation within the Danish Endocrine network has provided an op-

portunity for fruitful integration of research and test method develop-

ment, resulting in important new findings as well as regulatory interven-

tions. The Centre for Endocrine Disrupters has played a key role in this

work: it has applied research directed towards preventive work, includ-

ing regulation.

The network has organised meetings twice a year. Meetings have fea-

tured presentations by the authorities on new initiatives and topical

debates relating to testing, assessment and regulatory actions on EDs as

well as by researchers on new scientific results and general test method

issues. Network meetings have resulted in better communication and

understanding between regulators and scientists on multiple levels.

Scientific results have been better linked to their use in a regulatory

context, research has become more targeted in relation to regulatory

needs and press communication has been better coordinated between

the two groups. The meetings have also fostered communication and

understanding between scientists of various disciplines.

General assessment and decision making framework on EDC’s

The general approach for testing, assessment and management of sub-

stances with hazardous properties of special concern has been to dis-

criminate between substances that are “confirmed / regarded as”, “sus-

pected for” or having “potential for” such properties. Two categories


distinguish between ED in vivo (confirmed) (1) and suspected ED (in

vivo) (2a) or potential ED (in vitro / in silico) (2b).

The Nordic input to the OECD EDTA recommends that in the case of

an EDC in vivo and with the presence of risk, risk reduction by re-

striction of production/ use or authorisation should occur. With a sus-

pected EDC in vivo, preliminary risk assessment could possibly be ac-

companied by an additional assessment factor. If risk is perceived, soft

regulatory intervention should take place and/ or definitive testing and

evidence from industry should be required. Industry should thus be

incentivised to provide more confirmatory evidence. In the case of a

potential EDC in vitro / in silico, prioritisation for further investigations

should occur together with provision of supporting evidence and WoE

expert judgements.

“Strict” and “Soft” Management

Management is divided into two categories: “strict” and “soft”. Strict

management should be resorted to when the level of evidence is high

and the severity of the effect is large. Strict management should prefera-

bly translate to strong regulation at the EU level, including restrictions

and authorisation. Soft management should be applied while consider-

ing the level of evidence and the severity and nature of hazard and risk.

If suspicion results to be substantiated and the effects is severe, regula-

tory intervention at the national level should follow. Creating incentives

for the generation of confirmatory evidence is of great importance with-

in the realm of soft management.

General principles for soft regulatory intervention presented prescribe

avoidance of unnecessary use of the chemical and minimisation of expo-

sure. Furthermore, promotion of the generation of definitive evidence is

highlighted. To make these principles operational, communication and

advice to the public is encouraged and provision of incentives to industry

via development of alternative substances and promotion of voluntary

risk reduction agreements is recommended. On the EU level, promotion of

regulatory action is needed, especially for the generation of definitive date

and advancing regulation based on the precautionary principle.


1.3 The OECD Conceptual Framework on Endocrine Disrupters (Petteri Talasniemi, Tukes, FI)

The OECD Conceptual Framework (CF) is developed to provide a

framework for the testing and assessment of endocrine disrupters (EDs).

The framework works as a guide to the available assays for information

on EDs, including assays developed to test guidelines as well as assays

under development for screening and testing EDs. The original concep-

tual framework agreed in 2002 by OECD Task Force on endocrine dis-

rupters testing and assessment is being superseded in 2011 by an up-

dated version by the OECD EDTA Advisory Group.

The Conceptual Framework is included in Annex 1 of the ‘Guidance

document on standardised test guideline for evaluating chemicals for

endocrine disruption’ (under finalization at OECD EDTA AG). The guid-

ance document provides scope for guidance for regulatory authorities to

interpret results from assays included in the CF for testing and assess-

ment of EDs.

The Conceptual Framework includes validated or widely-accepted

assays (harmonized OECD and national test guidelines) for ED outcomes.

Some assays are included in the Conceptual Framework but not in the

Guidance document, or at times, only limited guidance exists. These limi-

tations in guidance stem from two sources: either there is insufficient

experience of their use (e.g. vertebrate lifecycle assays and in vitro thy-

roid function assay) or the assays do not offer significant advantages

over existing assays (e.g. fish hepatocyte vitallogenin function assay). As

the Conceptual Framework is subject to periodic revisions, it evolves as

a “living document”. Assays included in the Conceptual Framework are

defined precisely to facilitate the mutual acceptance of data (MAD).

The revised Conceptual Framework (2011) divides data and assays in-

to five levels, each characterised by the type of information it generates:

Level 1. Existing data and non-test information

Level 2. In vitro assays providing data about selected endocrine

mechanism(s)/pathway(s)

Level 3. In vivo assays providing data about selected endocrine

mechanism(s)/pathway(s)

Level 4. In vivo assays providing data on adverse effects on endocrine

relevant endpoints

Level 5. In vivo assays providing more comprehensive data on

adverse effects on endocrine relevant endpoints over more extensive

parts of the life cycle of the organisms


It is of note, that the Conceptual Framework is not a testing strategy to

be followed linearly from level 1 to 5, but can provide ideas about where

to start testing. The data generated at various levels have a range of dif-

fering applications and implications. The Guidance Document is used for

interpreting assay results, in line with the weight of evidence approach.

1.4 Revised OECD Conceptual Framework for Endocrine Disrupters and the draft OECD GD on testing and assessment of chemicals for ED (Henrik Tyle, Danish EPA, DK)

In introducing the revised OECD Conceptual Framework for Endocrine

Disrupters and the draft OECD Guidance on testing and assessment of

chemicals for Endocrine Disruptors (ED), the presentation reviewed

some of the implications for assessment of High Production Volume

Chemicals (HPVCs) for reproductive toxicity including ED.

For both mammalian and non-mammalian toxicology, level 1 of the

Conceptual Framework encompasses existing data and non-test infor-

mation. This includes physical and chemical properties (e.g. MW reactiv-

ity, volatility), all available (eco) toxicological data from standardised

and non-standardised tests and QSARs, other in silico predictions and

ADME model predictions.

Level 2 of the framework comprises of in vitro assays providing data

about selected endocrine mechanisms and pathways. Such mechanisms

include oestrogen and androgen binding affinity, oestrogen receptor

transcriptional activation, androgen or thyroid transcriptional activa-

tion, in vitro steroidogenesis and MCF-7 cell proliferation assays.

Level 3 consists of in vivo assays for selected endocrine mechanisms.

For mammalian toxicology, the Uterotrophic assay (TG 440) and the

Hershberger assay (TG 441) are utilised, whereas for non-mammalian

toxicology, an array of assays include Xenopus embryo thyroid signalling

assay, Amphibian metamorphosis assay (TG 231), Fish Reproductive

Screening Assay (TG 229), Fish Screening Assay (TG 230) and Androgen-

ized female stickleback screen (GD 140).

Level 4 of the Conceptual Framework consists of in vivo assays for

non-mammalian toxicology and the adverse effects on endocrine rele-

vant end-points. Tests include Fish Sexual Development Test (TG 234),

Fish Reproduction Partial Lifecycle Test, Larval Amphibian Growth &

Development Assay, Avian Reproduction Assay (TG 206), Mollusc Partial

Lifecycle Assays and Chironomid Toxicity Test (TG 218–219).


Level 5 is divisible into in vivo assays for mammalian toxicity and

non-mammalian toxicity. This translates to more comprehensive data on

the endocrine relevant endpoints over more extensive parts of the life

cycle of the organism for the former (e.g. Extended one-generation re-

productive Toxicity Study (TG 443), 2-generation assay (TG 416)) and

more comprehensive data on adverse effects on endocrine relevant end-

points over more extensive parts of the life cycle of the organism for the

latter (e.g. FLCTT (Fish LifeCycle Toxicity Test), Medaka Multigeneration

Test (MMGT)).

It was emphasised that the assessment of each chemical should be on

a case-by-case basis, taking into account all available information, bear-

ing in mind the function of the framework levels. The frameworks

should not be considered as all inclusive at the present time. At levels 2,

3, 4 and 5, assays are included that are either available or provisional, as

their validation is still under way.

REACH poses somewhat extensive tonnage triggered standard infor-

mation requirements on reproductive toxicity. A controversial question

however remains in whether the new TG 443, the Extended One-

Generation Reproductive Toxicity Study (EOGRTS) could be required in-

stead of the REACH requirements. There has been extensive discussion on

this in the Member State Committee (MSC) but no agreement has been

reached. The majority of MSC members do not think it is legally possible

to require EOGRTS because REACH specifically refers to “a two generation

reproductive toxicity test”. The Nordic countries also disagree on the is-

sue: Denmark advocates EOGRTS as a standard information requirement

under REACH while Norway, Sweden and Finland only accept the use of

EOGRTS under REACH if testing of F2 is triggered in all cases.

A CARACAL EOGRTS group has been established to mediate the disa-

greement. The group found that the EOGRTS is the most up-to date and

comprehensive repro-tox higher-tier test with a generally increased

sensitivity (number of analysed animals) and scope (range of new repro-

tox parameters especially on ED). The group agreed that no scientific

triggers relating to intrinsic properties can be identified for triggering

F2. The group agreed that DNT and DIT is default and can only be omit-

ted if not scientifically necessary. The group decided to recommend TG

443 to be included in the EU TM Regulation as soon as possible. Some

proposed ECHA to recognize TG 443 as appropriate in the meantime and

to revise REACH Annexes. Denmark sees these developments as highly

urgent and commendable due to the superiority of the EOGRTS test.


1.5 NM definition and substance identification (Emma Vikstad, Kemi, SE)

A definition for nanomaterial is imperative in a regulatory context. At

the moment multiple definitions exist, impairing the ability to discuss

the issue convincingly. In the Cosmetics Directive nanomaterials are

defined as “insoluble or biopersistant”, “intentionally manufactured” and

to be of “1 to 100 nm” of size. The Restriction of Hazardous Substances

Directive defines nanomaterials as “substances of very small size”, while

the Novel Food regulation finds them to have “discrete functional and

structural parts” of “100 nm or less” in size.

Towards a harmonised EU definition?

The Draft Commission Recommendation (article 2) on the definition of

the term “nanomaterial” (2010) finds that a nanomaterial is a material

that meets at least one of following criteria. Firstly, the material either

needs to consist of particles, with one or more external dimensions in

the size range from 1 nm to 100 nm for more than 1% of their number

size distribution, or secondly, to have internal or surface structures in

one or more dimension in the size range between 1 nm and 100 nm. The

additional criterion requires a specific surface area by volume greater

than 60 m2 / cm3, excluding materials consisting of particles with a size

lower than 1 nm. Public consultation on this recommendation took place

in 2010 and will hopefully soon lead to a harmonised EU definition.

Substance identification of nanomaterials under REACH

A debate on substance identification exists in parallel to that of the defi-

nition. CARACAL (Competent Authorities for REACH and CLP regula-

tions) has delegated substance identification of nanomaterials under

REACH to its sub-group, CASGnano, consequently creating the expert

group RIPoN1 on substance identification. The RIPoN1 project was aim-

ing to be strictly scientific and technical and remain apolitical while tak-

ing a bottom-up approach to “evaluate the applicability of the existing

guidance” and “if needed, to develop specific advice on how to establish

the substance identity of nanomaterials”. The RIPoN1 process has been

problematic from its premise, divorcing science and politics, onwards;

there have also been practical difficulties of differing starting points and

views within the group as well as the lack of a definition.

The single most prominent issue has been size as an identifier, acting

a triggering point for a new substance under REACH, versus size as a

characteriser, not amounting to a new substance under REACH but de-


termining the substance as a form of an existing substance. Consensus

was reached on carbon nano tubes not being graphites, constituting one

of the few issues where consensus was achieved. The RIPoN1 Advisory

Report published in March 2011 was followed by CARACAL consultation

and we are yet to see what action will follow from the Advisory Report

both in terms of the definition and substance identification.

1.6 Implementing REACH on NMs: EU guidance on NM safety assessment (Poul Bo Larsen, Danish EPA, DK)

The work on implementing REACH on NMs was presented and the out-

come of the three RIP-oN projects were discussed.

RIP-oN 1 Substance Identity

The conclusion from this project was that a policy decision has to be made

on whether size, surface area and surface treatment should be considered

as characterisers or identifiers for a substance. If size is an identifier then

this would require separate registrations for nanomaterials.

RIP-oN 2 Information requirements

The applicability of the existing test methods was evaluated and the

need for further/ additional relevant data for nanomaterials was as-

sessed. Overall very little concrete nanospecific guidance could be pro-

posed for inclusion in the REACH guidance documents. No specific test-

ing strategy for nanomaterials could be suggested. However, further

guidance on sample preparation and granulometry were proposed. Al-

together the project gives a good overview concerning our present

knowledge and how far we can go with recommendation on nano-

materials in relation to the various test end-points.

RIP oN3 Chemical safety assessment

The RIPon3 on chemical safety assessment aimed to give further advice

on the development of exposure scenarios; on operational conditions

and risk management/ mitigation measures, and exposure estimation. It

also addressed these in relation to hazard and risk characterisation in-

cluding derivation of DNELs and PNECs. Overall further guidance in rela-

tion to risk management measures, operational conditions and personal

protective equipment was given. The relevant exposure metrics were

recommended such as weight based, number based and surface based


particle concentration in air. Exposure estimation tools in general were

not available for estimation of air-borne exposure levels. The recom-

mendation is to use our general hazard characterisation approach for

nanomaterials using DNEL derivation and the existing default values for

assessment factors.

Overall much remains to be done in order to implement nanomateri-

als in REACH, as REACH has not been designed for nanomaterials. For

example, the tonnage based triggers for information requirements do

not seem to apply for nanomaterials. It may be more appropriate to have

a separate and more flexible regulation for nanomaterials in parallel

with REACH so that no changes in REACH would be necessary, and a

nanospecific testing strategy could be more easily implemented.

2. Break-out groups on the regulatory framework and the links between EDC and NM issues

Four break-out groups discussed pre-given questions relating to the

regulatory framework and links between EDC and NM issues. The con-

clusions from each group are presented below.

2.1 Decisions and guidance – proceed or wait for new scientific information?

Should we proceed with decisions and guidance or still wait for new scien-

tific information on NMs and EDCs?

Group A

We should not wait for new scientific evidence before acting but

proceed with regulation based on the information we have

A case-by-case treatment seems an unattractive solution: industry

requires stability to react and function efficiently

Even though an array of tests exists for nanomaterials, their

applicability and guidance need to be further considered

Group B

With regards to regulating EDCs two questions are of relevance: how

do EDCs disturb the hormone system and how does it relate to adverse

effects? As regulation cannot be based on endocrine action, a relation-

ship is needed between endocrine action and adverse effects. With

nanomaterials, it is the fundamental uncertainty that we are circulating

around. In the absence of a clear link to be established, the goals of

regulation are not straight-forward

With nanomaterials, we cannot wait for more information as we do

not know what we are waiting for. At the moment we are uncertain of


a multitude of factors, including what is exposure and what is it that

we are testing. Instead of waiting, we need to learn by doing and

engage in a process of iteration and use experience and consequent

better information to improve regulation and practice

Group C

At the moment we do not know much about NMs or what questions

to ask. Furthermore, the questions asked now may be different in a

few years time

However, we should not only focus on science but also consider the

regulatory basis. The basis for regulation and testing is less clear for

NMs than for EDCs

At the moment Carbon Nano Tubes are not classified and as they

differ from each other, there is variation of form and effects within

the same chemical

Should chemicals that we do not know about be placed on the

market? With asbestos, we only knew about its effects afterwards

We could turn the question around and state that industry is

responsible for the safety of their own products (and this REACH

principle applies also NMs); industry should wait for the proof that

NMs are safe and address the unknown concerns

In conclusion, we should not wait to act even if we do not currently

have all the answers

Group D

Nano

What information are we waiting for? Should we suspect that

nanomaterials act differently? Should the regulatory approach be pro-

active or passive? Are we waiting for the (epidemiological) hazard

evidence? The case of nanosilver is illustrative of these dilemmas

We are waiting for a definition – it is not possible to proceed before a

definition is accepted

There is political pressure to develop decisions and TGD on “nano”

We may not have seen scientific evidence on nanospecific hazards and

therefore there is no proof of the need to develop nanospecific TGD

We could start with deciding and developing guidance on a case-by-

case basis


EDCs

We are already engaged in the decision-making process and guidance

development, but we need to focus on development and validation of

the testing strategy and commonly agreed criteria

Summary

The view that we should not wait for more scientific information before

going forward with decisions and guidance prevailed across groups. In

the case of nano, high uncertainty and lack of clarity on what further

information is needed strengthened the case for swift regulatory action.

For EDCs, the basis for regulation and the state of the knowledge seemed

better-defined.

2.2 Definining EDCs and NMs

Do we have an adequate science based definition for EDCs and NMs?

Should the definitions be scientific or purely practical?

Should the EDC definition cover all hormonal modalities (effects related

to immunotox and metabolia)? Should we have a single common

definition for NMs in all legislation?

Group A

The lack of definitions constitutes a major deficiency

The process of creating a definition was seen to be hampered by

industry and the lack of definitions a potential excuse for inaction

The scientific disagreement that currently prevails would suggest

that a potential definition needs to be practical. Nevertheless,

definitions should have a scientific basis, especially for the sake of

measurability. The practical unit for measurement also needs to be

carefully considered

An EDC definition should cover all hormonal modalities

Group B

When choosing between approaches to defining nano, the practical

approach is preferred. Better definitions will eventually follow from

regulatory action

Concern was expressed that in the case of nano, we are defining

something that you cannot define. Therefore dealing with specific

cases, learning by doing and ultimately taking a bottom-up approach

to criteria and definition seem correct


A definition is imperative; even as a starting point for regulatory action

The 2010 Commission draft recommendation on nanomaterial

definition was a positive development that could be adopted

Discussion on potency of effects and criteria was discussed. Perhaps,

both for NMs and EDCs, you have to regulate those problems which

are most obvious: what do we know, what are we most concerned

about and start regulating there

Group C

The definition should be based on science but should simultaneously

be practical for the regulatory context

Industry is against the 1% limit (in the draft Commission

recommendation) because it claims that then all of their products

would contain NMs

The philosophy is different behind the definitions for EDCs and NMs

– for EDCs the focus is on the mechanisms, while for NMs it is the

description of material that matters

The definition for NMs should be general. Different regulations

(cosmetics, food etc.) could then have specific amendments to the

general definition

For medicine, the definition is less important than for other products,

as it is so extensively tested and strictly regulated

For EDCs, all hormonal modalities should be covered in the definition

Group D

Nano

The Significant New Use Rule (SNUR) in the US EPA was proposed as

an example to illustrate how to handle and separate NMs from the

bulk substance

We need a definition that is both science-based and practical

From the scientific point of view there are criteria for a definition

From the political point of view there is resistance to use such a definit-

ion due to economical and sociological consequences (public opinion)

EDCs

A definition should cover all hormonal modalities. Nevertheless, it

needs to be recognized that the consequences of this could be drastic

as numerous effects could be considered as EDC effects


Summary

All groups saw an imminent need for a nanomaterials definition to allow

regulatory action to take place. A practical approach to the definition

was favoured in the current situation of persistent uncertainty. The sci-

entific basis should however be incorporated into this practical ap-

proach. Break-out groups also agreed on the need of an EDC definition

covering all hormonal modalities.

2.3 REACH – regulating EDCs and NMs

Can REACH take care of EDCs and NMs without any revisions?

Should only guidance for the registration and safety assessment be

revised and updated?

Are new annexes to REACH needed for EDC criteria?

Should there be a revised annex VI for NM identification as its own

substance (size and form as additional identifiers)?

Group A

Currently, REACH lacks specific reference to nano, indicating that

revision is needed

Even though REACH claims to cover all forms of chemicals, inventory

of data submitted to dossiers shows that very little data on nano has

been submitted

We need to decide whether REACH is the right framework for

regulating nanomaterials and consider whether there any

alternatives to it

Can the Nordic group have influence over amending REACH?

A definition is necessary for the development of any regulation

There are no specific data requirements for EDCs identification in

REACH. Cocktail effects constitute a larger concern

Perhaps new annexes could be part of the solution. Current work on

annexes includes EDC criteria

Group B

Nanomaterials are not chemicals in the normal sense and therefore

regulation by REACH is complicated. Even though tonnage levels are

far too high for nanomaterials, some specific nanomaterials could be

regulated by REACH and its scope could then be gradually expanded

As the Commission seems to prefer making no changes to

regulations, changing annexes seems a feasible, lighter mechanism as

opposed to major amendments


Further problems in adjusting REACH to nanomaterials are numerous.

Change in regulation would be difficult due to the EU Parliament and

Council; nano discussion is not mature enough to address the standard

data requirements of tonnage triggers and whether nanoforms are

phase-in substances. Thus problems in relation to substance identity

(enzymes, macromolecules, mixtures) abound

It was also noted that it is most important to ensure adequate safety

assessment of all forms and uses of the substance. Whether the NMs

are registered as separate substances or together with the bulk form

(dossier within dossier), may not be an issue

Group C

In REACH the changes could be made via ATPs (amendment to

technical progress) to Annexes, as the Commission is unlikely to open

up the REACH legal text for changes. Guidance is made by ECHA and

is not legally binding

For NMs, changes in the Annexes I (safety assessment) and VI

(information requirements) should occur instead of guidance

For EDCs, guidance would be a good idea, even though classification

should also be discussed. There should first be a new REACH Annex

for EDC criteria, similarly to Annex XIII for PBTs. Perhaps after that it

could get into the CLP through the GHS (Globally Harmonised System

of Classification and Labelling Chemicals)

Group D

In the case of nano, REACH will need revisions

Guidance to the regulation and updated safety assessment are not

sufficient measures. There is a need to revise the main text and the

Annexes, and perhaps include an additional Annex (e.g. on

identification)

The question with reference to EDCs was not within the group’s

expertise

Summary

Even though there was no consensus opinion on how the REACH regula-

tion could ensure the safety of NMs, participants agreed that further

measures to ensure safety are needed. Potential methods for ensuring

that NMs are addressed separately from the bulk substance include

amending the regulation or providing new or revised annexes or ade-

quate ECHA guidance for registration. It was seen that for the identifica-

tion of EDCs under REACH, a new Annex on EDC criteria, alike to the

annex for PBT criteria, was probably necessary.


2.4 Registration of NMs

Should NMs be generally registered as new substances separate from the

bulk substance, or should it be left up to the registrant how to handle them?

Group A

Sticking to the bulk form may yield more information

Group B

Whether NMs in question are phase-in or new substances is relevant

to the question

With reference to whether registration should be left up to the

registrant, it seems that industry cannot be held responsible

backwards in time

Group C

There is a tendency to support separate registrations for the bulk and

NMs

Substance identification has to be extended

If bulk and NMS were to be registered separately, would the total

volume and consequently the information requirements for NMs be

reduced? Also, would there be separate registration fees?

Could this separation of bulk and NMs be done by changing the

guidance? This question connects to the previous one: changes in the

Annexes I (safety assessment) and VI (information requirements)

should occur instead of guidance. Methods of evaluation could

however be handled in the guidance

Group D

NMs should be registered as separate substances unless specific

evidence provided shows the opposite

Summary

There was a strong general feeling, that it would be safer to always reg-

ister NMs as new substances with nano-adapted data requirements.

Nevertheless, other adequate means, such as better ECHA guidance on

registration, were supported.


2.5 Adequacy of existing legislation to regulate confirmed EDCs

If a substance can be considered as confirmed EDC are the regulatory

actions in new biocide, PPP and REACH regulation adequate?

Group C

The regulations are adequate to some degree: under the Reprotox

1A/B classification, we have the tools to regulate

However for the combined effects, regulations are not sufficient

because chemicals are under a different regulatory framework

N.B. Groups B and D did not answer the question due to time

constraints

Summary

The existing regulatory tools were generally considered adequate. How-

ever, the combined effects of EDCs from different sources were per-

ceived as difficult to tackle.

2.6 A practical example on NMs REACH registration of Nano Fibril Cellulose

How would you handle the REACH registration of Nano Fibril Cellulose, as

bleached pulp is exempted from registration (annex IV, Cellulose Pulp):

if it is manufactured from cellulose pulp mechanically

if it is coated by adsorption e.g. by PVA

if it is chemically modified?

Group C

If it is manufactured from cellulose pulp mechanically, it depends on

the level of change

If it is coated by adsorption (e.g. by PVA), it becomes a borderline case

If it is chemically modified, it should be taken out from the

exemptions

N.B. Groups A, B and D did not answer the question due to time

constraints

3. Presentations on test guidelines and their applicability to assess NMs

3.1 What TG tools we have, and which TGs and GDs have to be developed for NM testing (Peter Kearns, OECD EHS/ENV)

Mutual Acceptance of Data and the OECD principles of Good

Laboratory Practice

The principle of Mutual Acceptance of Data (MAD)is defined in the OECD

Council Decision on Mutual Acceptance of Data in an Assessment of

Chemicals C(81)30(Final) as follows:

“Decides that the data generated in the testing of chemicals in an OECD Mem-

ber country in accordance with OECD Test Guidelines and OECD Principles of

Good Laboratory Practice shall be accepted in other Member countries for

purposes of assessment and other uses relating to the protection of man and

the environment.”

The OECD principles of Good Laboratory Practice (GLP) enforce a single

quality standard for test facilities throughout OECD, applied for testing

of all chemical substances. It is linked to a management tool that ad-

dresses the responsibility and requirements for a test facility’s organisa-

tion and personnel, quality assurance programme, physical plant, appa-

ratus, materials and reagents. Principles governing conditions, proce-

dures and performance are also provided. Good laboratory practice in

combination with the use of OECD test guidelines leads to Mutual Ac-

ceptance of Data.

The benefits of Mutual Acceptance of Data include avoiding duplica-

tion of testing by industry: the consequent cost savings amount to as

much as 150 million euros a year. In addition, the principle reduces non-

tariff trade barriers as MAD Council Decisions are open to selected ad-

hered non-members. There are approximately 150 test guidelines with

guidance on physical-chemical properties, human toxicity, ecotoxicity,

bio-degradation and accumulation and pesticide residue testing.


OECD Working Party on Nanomaterials

The OECD Working Party on Nanomaterials was established in September

2006. It aims to promote international co-operation on the human health

and environmental safety of manufactured nanomaterials. It also involves

the safety testing and risk assessment of manufactured nanomaterials

under the OECD Sponsorship Programme. The programme consists of two

phases: Phase 1 launched in 2007, tested selected NMs for the selected

endpoints, whereas Phase 2, planned to commence in 2011, will consider

cross-cutting issues and the need for further tests that are identified in

Phase 1. Phase 1 of the Sponsorship Programme is expected to be com-

pleted in mid-2012. WPMN achievements include publishing the Prelimi-

nary Guidance Notes for Sample Preparation and Dosimetry (GNSPD) and

a review for further GD development or updating TGs.

3.2 REACH and Information Requirements for safety assessment (Jukka Ahtiainen, Tukes, FI)

New information and endpoints for NMs

The question of whether new information and endpoints are needed for

NMs was raised. In the case of degradation and bioaccumulation, the

existing test for detection is deemed sufficient. For physical-chemical

properties, new information and endpoints are however necessary. For

toxicology and ecotoxicology, many of the existing endpoints seem ade-

quate even though some additional endpoints could be considered.

Applicability of OECD Test Guidelines for NM testing

With regards to the applicability of the OECD Test Guidelines for NM

testing, biological “endpoints” or measurement variables are found rele-

vant and applicable. The number of offspring in reproduction tests, bio-

accumulation into tissues and CO2 production in the biodegradation test

are examples of applicable biological endpoints. It was noted that dosing

of the test material and test media affects both exposure and consequent

effects. NM detection and characterisation were seen very important at

the start and during the test. It thus follows that relevant dose metrics

should be used (mg/L or surface area or particle number) and that ter-

minology has to be clear (e.g. dissolved (Ag+) or dispersed (Ag-

nanoparticles); agglomerate and aggregate).

Conclusions on the methods for biotic effects and fate were to rec-

ommend following the best guidance available. In addition, careful re-

cording of all the details of the process was prescribed to enable retro-


spective analysis. Finally, detecting and characterising the NM exposure

to the best ability at every step of testing was encouraged.

If the measured variables in the existing Test Guidelines are NM-

relevant, the use of Test Guidelines needs to be contemplated. Possible

developments could include a whole new set of Test Guidelines for NM

testing or a suite of Guidance Documents to use the existing TGs. Ensur-

ing the mutual acceptance of data is also of utmost importance while

considering such developments. The creation of a conceptual framework

for NM testing and assessment, in the style of the EDC Conceptual

Framework could be another step to be taken. If measures to develop

guidance were to be taken, their position within the REACH regulation

needs to be considered. Options for this include having a separate annex,

integrating nano-specific guidance to the ECHA registering guidance or

alternatively having totally different guidance, separate from REACH.

3.3 OECD Sponsorship Programme and NM testing (Sjur Andersen, KLIF, NO)

The OECD WPMN sponsorship programme is currently examining 13

different nanomaterials with regards to their physical-chemical proper-

ties, environmental fate, human and environmental properties. The pro-

gramme has two phases: Phase 1 for information gathering and Phase 2

for acquiring data for risk assessment. Part of the program aims to pro-

vide input to another group that addresses potentially necessary chang-

es to the OECD Test Guidelines when testing nanomaterials. The Spon-

sorship Programme is based on voluntary contributions – at the moment

the USA and the EC have the lead. The Nordic countries contribute to the

examination of nanosilver and the funding is provided by the Nordic

chemicals group. A table of the currently tested materials and the level

of contributions is presented below.


Table 1: Contributions to the OECD Sponsorship Programme

OECD set of materi-

als tested

Level of sponsorship

Lead sponsor(s) Co-sponsor(s) Contributor

Fullerenes (C60) Japan, US China, Denmark

SWCNTs Japan, US Korea, BIAC for MWCNT Germany, BIAC, Canada, EC,

France, China

MWCNTs

Silver nanoparticles US, Korea Germany, Australia, Canada,

Nordic Council of Ministers

EC, France, China, Netherlands,

BIAC

Iron nanoparticles China BIAC US, Canada, Nordic Council of

Ministers

Carbon black

Titanium dioxide Germany,

France

Austria, Canada, Spain,

BIAC, Korea, US

China, Denmark, UK

Aluminium oxide Germany, US

Cerium oxide UK/BIAC, US Netherlands, Australia, Spain

Germany, EC, Switzerland

Zinc oxide BIAC Australia, Spain, US

Canada, Denmark, Japan

Silicon dioxide EC, France BIAC (CEFIC), Belgium, Korea

Denmark, Japan

Polystyrene

Dendrimers Spain, US Austria, Korea Spain, US Austria, Korea

Nanoclays BIAC US, Denmark, EC

Nanogold South Africa Korea, US EC

3.4 Nordic nanoAg contribution to the Sponsorship Programme (Janneck Scott-Fordsmand, DMU, DK)

The Nordic countries have established a collaborative testing programme

to contribute to the OECD WPMN Sponsorship Programme. The Nordic

test programme has tested the ecotoxicity of nano-silver nanomaterials in

soil and sediment. The lack of studies in the soil environment, the wide

range of species and endpoints involved, incoherence in guideline use,

limited reporting of parameters (TEM, SEM, DLS) and scattered results

have all motivated this work. Broad aims and results will include broaden-

ing expertise, increasing input to the sponsorship programme and en-

hancing coordination, also to form a network that can support Nordic

agencies. The testing programme also aims to develop test guidelines

(TGs) that are capable of dealing with nanoparticles (NPs) and to test


OECD TG 222 (soil) and TG 225 (sediment) for NPs and make suggestions

on their adaptions. Especially the hypothesis that sediments and soils will

act as sinks of NMs in the environment has motivated this work.

The approach of the test programme has been to combine tests of

two TGs with worms while testing fundamentals with NPs in the TGs.

Studies have also examined particle size and particle coating. Denmark

(Scott-Fordsmand et al) has tested TGG 222 on the mortality and repro-

duction of earthworms, while Finland has been working with TG225 and

the mortality and reproduction of sediment worms (Kukkonen et al).

The Norwegian contribution (Oughton et al) has been on fate and uptake

in organisms whereas Sweden (Hasselov et al) has concentrated on de-

tection and characterization of NMs during exposure.

On the basis of the Nordic testing programme, developing methods

further is seen necessary. As sediment and soil effects are not compara-

ble, comparability remains an issue. Furthermore, the quantification of

exposure is a major concern to be addressed. Even though challenges

persist in testing nanoparticles, there is a case for optimism and we

should go forward with further testing. For example, results indicate

that direct addition as dry powder into soil gives the best homogenic

distribution of the material.

As response to the the presentation, a representative of the EC com-

mented that testing should prioritise NMs being sold – at the moment

there are however few relevant NMs on the market.

3.5 Environmental fate studies on NMs (Erik Joner, Bioforsk, NO and Deborah Oughton, Norwegian University of Life Sciences, NO)

In this joint presentation Erik Joner first discussed the issue of environ-

mental fate of NMs during the lifecycle, especially when they become

waste. One of the questions was: are there nanospecific issues in the

environemental fate of NMs. Again the soil compartment and effects

seen in the earthworms seemed relevant. Testing in more relevant soil

conditions including “ageing” was concluded to be important. In the soil

studies clear effects of nano-iron (nZVI) have been seen on the plant

emergence and growth. Also nano-silver seemed to cause apoptosis in

the earthworms.

Deborah Oughton presented observations with silver-NMs in aquatic

fate studies and effects seen in fish. It seems that nanoparticles (Ag) stay

stable and dispersed especially in the Nordic humic soft waters. In par-


ticular, the possibilities to use neutron action as a method to detect me-

tallic NMs were discussed. The presentation also showed some results

from former studies of release of particles and ions from Chernobyl ac-

cident, which can be taken as useful examples for fate studies in soil and

water. In these, nano-specific issues like changes in agglomera-

tion/aggregation, dissolution and time-course effects of ageing in soil

were emphasized.

3.6 Detection of NMs in the environment and verification of exposure (Geert Cornelis, University of Gothenburg, SE)

Environmental risk assessment of engineered nanoparticles requires

physico-chemical characterization of their particle number concentra-

tion and aggregation state in environmental media. Nevertheless, availa-

ble analytical techniques are often contradictory or are not suited for

determining environmental concentrations. Two techniques were pro-

posed for sensitive and specific analysis of engineered nanoparticles in

complex environmental media: field flow fractionation (FFF) combined

with inductively coupled plasma-mass spectrometry (ICP-MS) and single

particle ICP-MS (SP-ICP-MS).

Promises and limitations in terms of detection limits and dissolved

background of these techniques were detected using acquired data on

engineered citrate coated silver nanoparticles with sizes ranging be-

tween 20 nm and 80 nm in the case of SP-ICP-MS.

Two first examples of analysis in the environment were shown. While

the presented techniques show great potential, detection limits in terms

of size are limited to 20 nm – 40 nm in the case of AgNP, especially when

a dissolved background is present. Possible prospects for improvements

were discussed of SP-ICP-MS. FFF or centrifugal-FFF (cFFF) coupled to

SP-ICP-MS may provide additional information on the state of the engi-

neered nanoparticles of which both fate modelling and exposure dose

verification in the case of ecotoxicology can benefit.

The interactions of nanoparticles (NPs) and the environment were

also discussed, examples including homocoagulated/heterocoagulated

NPs. The partial or full sulfoxidation and effects of this on fate and toxici-

ty have been illustrated in silver-NPs studies in Australia.


3.7 Inhalation of nanoparticles and health effects (Marit Låg, Norwegian Institute of Public Health, NO)

Nanoparticles (less than 100 nm) constitute the smallest fractions in

ambient particulate matter (PM). Although the health effects of PM are

confirmed by several studies, it is still uncertain which fraction of the air

pollution is responsible for the various health effects. However, epide-

miological studies indicate that the nanosized particles may have a role

in particular with respect to cardiovascular effects. Inflammation is re-

garded as an important process in development and aggravation of both

lung- and cardiovascular diseases induced by PM.

Studies on deposition of inhaled particles in the lungs of rats show

that particles in the nanosize range were retained in the lung, but they

are also translocated to the interstitial tissue more readily than larger

particles. Especially the particles in the 10–100 nm size range seemed to

reach the alveolar system. It seems, however, likely that two or more

mechanisms of toxicity are involved in mediating heart disease by na-

nosized particles: i) indirect effect of pulmonary inflammation and oxi-

dative stress ii) translocation of particles to the circulation and a direct

effect on cardiac cells or endothelial cells.

Furthermore, nanosized particles have a more pronounced effect on

inflammation, cell damage and cell stimulation than equal mass of parti-

cles of the same material of greater size. The higher surface area seems

to be the metric driving the pro-inflammatory effects. This appears to

hold true for several different materials such as carbon black, titanium

dioxide, various metals and polystyrene. In addition to surface area also

shape, structure and chemical composition of the nanoparticles are im-

portant parameters for eliciting inflammatory responses. In alveolar

inflammation the release of IL-6 (inflammatoric mediators), immune

cells and ROS may lead to inflammation and to the various diseases.

Many nanoparticles seem to be mildly inflammagenic, however, they

may augment lung inflammation related to pre-existing diseases such as

allergy, chronic obstructive pulmonary disease (COPD) and microbial

infections. Also new endpoints for the inhalation studies should be con-

sidered e.g. BAL bronchious alveoli lavage analysis.

In conclusion, it is no doubt that engineered nanoparticles have a po-

tential to elucidate health effects. Their toxicity will also depend on the

exposure to these particles.


3.8 Update on genotoxicity of NMs (Julia Catalán, FIOH, FI)

Genotoxicity testing of engineered nanomaterials (NMs) involves a

number of challenges. It is often not known how much of the material is

taken up by the cells and if differences in intracellular pathways could

explain differences in genotoxicity. The basic mechanisms (e.g. direct

interaction with DNA, indirectly through ROS reaction and inflamma-

tion) of NMs genotoxicity were presented. It seems that direct interac-

tion, for example access into nucleus or actions during cell division, and

possible “Trojan horse effects” releasing the ions inside the cell seem to

be possible. The genotoxicological methods that have been used in test-

ing NMs in vitro and in vivo, considering their applicability for this pur-

pose were summarized. Finally, the FIOH contributions to ongoing EU

projects aiming at standardising toxicity testing of NMs were presented.

3.9 In vitro studies in NM testing - Experience from NanoTEST (Lise Fjellsbø, NILU, NO)

Nanoparticles (NPs) with their unique beneficial properties also cause a

safety concern as their possible impact on human health is not known. A

better understanding of how properties of NPs define their interactions

with cells in exposed humans is a considerable scientific challenge. The

FP7 project NanoTEST evaluates interactions of well characterized NPs

with biological systems by studying the uptake and transport of NPs

through biological barriers, and by addressing key endpoints of cytotox-

icity, oxidative stress, inflammation, immunotoxicity and genotoxicity.

We study the effects of NPs in several target systems derived from dif-

ferent biological systems: blood, vascular system, liver, kidney, lung,

placenta, digestive, and central nervous systems by evaluating existing

and developing new in vitro assays. The final goal is to develop alterna-

tive testing strategies essential for detailed risk assessment, applying

high-throughput in vitro methods.

There are a number of different NP characteristics which may influ-

ence transport and toxicity, including size, surface area, coating and

charge. In NanoTEST we find detailed characterization of the NPs very

important to be able to compare toxicity results across different labora-

tories, and also to better understand their behaviour and mechanisms of

action. Seven NPs have been characterized and tested; PLGA-PEO poly-

meric NPs (140 nm, ADVANCELL), uncoated iron oxide and oleate coat-


ed iron oxide (Fe3O4 , 8+3 nm core, PlasmaChem), titanium dioxide (TiO2,

21nm, Evonik), fluorescent (Rhodamine) silica (25 and 50nm, Micro-

spheres-Nanospheres ) and Endorem (Guerbet) as a negative control.

Until now, several in vitro methods have been investigated and/or

adapted for NP testing; Fe uptake, Neutral red uptake, MTT Test, ROS

production, LDH Assay, WST-1 Assay, 3H Tdr incorporation, TUNEL,

glutathione thiol detection, ELISAs for cytokines and growth factors,

Propidium iodide, HE, DCFDA, growth activity test, plating efficiency,

signaling pathways, in vitro micronucleus test, comet assay for detection

of strand breaks and specific DNA lesions and others. To be able to com-

pare data, partners used NPs from the same batch, followed the same

dispersion protocol and the same experimental design of 5 concentra-

tions (to obtain a dose response) in each treatment. In all experiments

quality controls and standards were used. Data are complete for most

assays with all NPs.

3.10 Aquatic effects and fate of nanomaterials in the Nordic environment (Jussi Kukkonen, University of Eastern Finland, FI)

Examples of effects of fullerene and nanosilver in water or sediment

tests on Daphnia magna and two benthic organism, Lumbriculus varie-

gatus (Oligochaeta) and Chironomus riparius larvae, were presented and

discussed. It was noted that NMs are not chemicals as such, and testing

of them include many challenges.

Fullerene agglomerates were prepared using a water stirring method.

Fullerene accumulation into D. magna was rapid during the first few

hours, and based on accumulation modeling, 90% of the steady-state con-

centration was reached in 21 h. After exposure for 24 h to a 2 mg/L fuller-

ene solution, the daphnia accumulated 4.5 g/kg wet weight. Daphnids

exposed to 2 mg/L fullerenes for 24 h eliminated 46 and 74% of the ac-

cumulated fullerenes after depuration in clean water for 24 and 48 h, re-

spectively. Transmission electron microscopy revealed that the majority

of the fullerenes present in the gut of daphnids were large agglomerates.

L. variegatus were exposed to 10 and 50 mg fullerenes/kg sediment

dry mass for 28 d. These concentrations did not impact worm survival or

reproduction compared to the control. Feeding rates were also slightly

decreased for both concentrations indicating fullerenes’ disruptive effect

on feeding.


Chironums riparius were exposed after allowing suspended fullerenes

to settle down creating a layer of nC60 on top of the sediment, another

environmentally realistic exposure method. To test the hypothesis that

higher food concentrations will reduce toxic responses, two food concen-

trations were tested (0.5% and 0.8% Urtica sp.) in sediment containing

fullerene masses of (0.36 to 0.55) mg/cm2 using a 10-d chronic test. In the

0.5% food level treatment, there were significant differences in all growth-

related endpoints for fullerene exposed organisms compared to controls.

Fewer effects were observed for the higher food treatment. Fullerene

agglomerates were observed by electron microscopy in the gut but no

absorption into the gut epithelial cells was detected in either organism.

Electron micrographs of L. variegatus also indicated that 16% of the

epidermal cuticle fibers of the worms were destroyed in the 50 mg/kg

exposures, which may make worms susceptible to other contaminants.

For C. riparius, microvilli were damaged and significantly shorter. The

potential toxic effects of fullerenes to C. riparius appear to be caused by

physiological changes.

4. Break-out groups on test guidelines and their applicability to assess NMs

Three break-out groups discussed pre-given questions on test guidelines

and their applicability to assess NMs. Two of the groups focused on toxi-

cology, while one concentrated on ecotoxicology. Their conclusions are

presented below.

4.1 Existing test guidelines and new guidance for the hazard and safety assessment of NMs

Can we manage hazard and safety assessment by using existing test guide-

lines or only by developing new technical guidance on how to handle and

characterise the exposure to NMs?

Toxicology group 1

We have to start with existing test guidelines to gather experience.

Guidelines can then be modified if necessary

While developing guidelines is imperative, more common knowledge

is needed to achieve comprehensive results

We need to decide what extensions are necessary in order to establish

whether existing guidelines are valid for nanoparticles (NPs)

Determining whether the OECD test guidelines are suitable to be

used for NPs is necessary

Plans for testing in vitro tests exist. This can be achieved only by

developing new technical guidance which will be a laborious endeavour

Normally in vitro tests are used to assess genotoxicity. However,

currently in vivo tests are needed to assess genotoxicity of NMs. It thus

follows, that the same thinking cannot be applied to chemicals and NPs

Some of the existing tests are compatible with NPs but there are also

many that are not applicable to NPs. Practical problems with NPs remain

in these tests, including removal of the interference of NPs with the

endpoint detection from the tests. This makes exposure problematic


At the moment, testing takes a case-by-case approach. With NPs, a

more flexible approach is needed

Toxicology group 2

Hazard and safety assessment can be managed if the new technical

guidelines address physical interaction, including agglomeration

In vitro assays can be used only for genotoxicity

Preparation of samples for exposure is important

It is most important to characterize exposure, instead of being too

specific in the guidelines

Ecotoxicology group

While existing guidelines are adequate for hazard and safety

assessment to some extent, traditional endpoints may be insufficient

with NMs

There is some need for modification but the existing test guidelines

provide a good starting point

Particle characterization must be ensured. Constant exposure is

impossible, so modifications must account for this

Is TG acceptance just a question of managing exposure? Alternatively

is it about the preparation of NP samples? Should an agglomeration

test be imposed?

Matrices are a further challenge. How are NPs to be mixed into

matrices? Should reference compounds exist for NPs?

Should test duration be extended to account for slower uptake? NPs

age differently in soil compared to traditional chemicals (increase

rather than decrease). Furthermore, speciation over time is

important to describe. Bioaccumulation needs to be regarded from a

new standpoint: revision is underway anyway

Longer test duration was recommended to better adapt to NPs.

Should different aspects be classified as optional and mandatory?

Summary:

Groups agreed that while development of guidelines is necessary, exist-

ing guidelines are an adept starting point for safety and hazard assess-

ment. Flexibility in guidance was emphasised by all groups. The exist-

ence of technical and conceptual challenges to the existing guidelines

was also observed.


4.2 Technical guidance for specific areas of testing

Should technical guidance be developed for specific areas of testing e.g.

soil studies, aquatic studies or inhalation and skin absorption studies?

Toxicology group 1

At the moment, generalisation is difficult and proceeding case-by-

case with NPs is preferable

General issues to be addressed include characterisation, size, size

distribution and dosimetry among others

Guidance should be flexible

Instead of requiring adherence to strict technical guidance, guidance

could allow some freedom of choice with recommendations on

procedure

Controls (positive/negative) are important

Trouble shooting notes would be good practice in order to collect and

share experiences from tests conducted

Toxicology group 2

The property of exposure needs characterization

Each type of exposure should have separate guidance

Ecotoxicology group

Soil/sediments and aquatic environments cannot be covered by the

same TG

Summary

While one of the groups elaborated their views at more length than the

others, there was agreement that different guidance for different areas

of testing is needed.

4.3 Guidance based on NM groups

Should guidance be based on NM groups (e.g. metal, metal oxide NMs)?

Toxicology group 1

Guidance should be based on NM groups if nanomaterials (NMs) can

be grouped in a meaningful way

Grouping may be practically difficult and thus faces the risk of being

misleading


Grouping is commendable if it is possible by using physico-chemical

characteristics

Would specific guidance then exist for metals and carbon nanotubes?

NPs cannot be grouped yet, at least in the case of metals

Even though uncertainty remains an issue, some data is appearing.

Metal NPs may have similar features (e.g. the ion release), while

similar carbon nanotubes have similar features

Toxicology group 2

NM groups do not seem the best basis for guidance

Nevertheless, grouping could be beneficial for compounds for which

enough specific knowledge exists

The success of grouping depends of the broadness of the guidance

document

Relevance of grouping NMs is questionable

Ecotoxicology group

Organic/inorganic and different uses (e.g. suspensions, powders) are

possible bases for NM groups

Dealing with coatings is problematic

From a regulatory viewpoint organic/inorganic is not useful.

Grouping based on use, volume or properties could be better for

regulatory purposes

Summary

Agreement on the practical difficulty of grouping nanomaterials existed

across all groups. Nevertheless, it was seen that if grouping could over-

come these practical hurdles, it would be desirable.

4.4 Nanospecific endpoints

Are there new nano-specific or nano-relevant endpoints in the areas of

physico-chemical properties, environmental fate (degradation and

accumulation), ecotoxicology or human health effects?

Toxicology group 1

The specific endpoints for NPs remain unclear. Options include

surface parameters, zeta potential, crystal form,

aggregation/agglomeration, size and size distribution

Also media should be characterized, including protein content in media

Characterisation should be done for the NM product in test media


With regards to human health effects, we lack guidelines. For

example, where do the particles go in the inhalation exposure

(adsorption, metabolism etc.)?

Some endpoints on the abiotic degradation, such as hydrolysis, are

relevant for NMs but at present can be waived as they are not

required under REACH for certain substances (e.g. metals)

Toxicology group 2

Surface reactivity is a potential concern with regards to physico-

chemical properties

The distribution of nanoparticles in the body is a potential new

endpoint that demands analyzing equipment

More sensitive endpoints could include gene expression and proteomics

N.B. Ecotoxicology group 1 did not answer the question due to time

constraints

Summary

Clear conclusions on new nano-specific endpoints failed to emerge.

However, many of the toxicological, ecotoxicologican and environmental

fate endpoints are nanorelevant. New endpoints and test methods are

needed for physic-chemical characterization of NMs.

4.5 Test Guideline Modification and the Mutual Acceptance of Data

How do potential modifications of the test guidelines affect the Mutual

Acceptance of Data (MAD)? How much can we divert from the standard

test guidelines?

Toxicology group 1

If the modification is added to the guideline it will be in line with

MAD (mutual acceptance of data)

Maybe a special solution could be used for NMs to speed up the

process of MAD

N.B. Toxicology group 2 and Ecotoxicology group 1 did not answer

the question due to time constraints

5. Presentations on the regulatory possibilities for EDCs and NMs

5.1 Outcome of the three Nordic workshops on EDCs held in Denmark in 2010 (Sofie Christiansen, DTU, Pia Juul Nielsen and Rikke Holmberg, Danish EPA, DK)

The joint presentation provided an overview on the conclusions of three

Nordic Workshops held in Denmark in the autumn of 2010.

A typology for EDC criteria as confirmed, suspected or potential en-

docrine disruptor was presented. Combined effects, the topic of one of

the workshops, including dose addition with the recommended model

were discussed. The discussion also addressed risk assessment quota

from different sources for one chemical. The extra safety factor of 10

was seen important.

Another workshop addressed risk communication and soft regulatory

measures. The workshop had reached the conclusion that the public should

always be consulted in creating legislation. The Nordic countries’ experi-

ences with soft regulatory measures further supported this conclusion.

The final workshop on the regulation of combined effects also out-

lined the status of EU work. It was noted that there is currently a compi-

lation of reports and on-going work. A forthcoming EC report assessing

existing legislation is expected to relate how legislation can address

combined effects. In addition to the EU work, the World Health Organi-

sation (WHO) framework remains an important source of expertise.


5.2 Regulation of combined effects – status of the EU work (Rikke Holmberg, Danish EPA, DK)

The presentation reviewed the status of work being done in the EU on the

regulation of combined exposure to chemicals from different sources and

pathways. Terminology and methods used to assess risk from combined

exposure were presented. Important, recent reports within the field were

also highlighted. The recent draft opinion regarding chemical mixtures from

the 3 scientific committees in the EU and the 4th report on the implementa-

tion of the Community strategy for endocrine disrupters were also ad-

dressed. The Danish view on critical issues within the field and possible

ways forward under the upcoming Danish Presidency were highlighted

5.3 Registration of ZnO in REACH – is it sufficient for safety evaluation of nano ZnO? (Katarzyna Malkiewicz, Kemi, SE)

An overview of the practical training in toxicological risk assessment

(RA) of chemicals realized at the Swedish Chemicals Agency (Kemi) as a

part of European Toxicology Risk Assessment Training (TRISK) was

presented. The work in this project had double focus: to analyze toxicity

data registered for Zinc Oxide (ZnO) at ECHA within REACH and discuss

the approaches for RA taken by the industry; and to collect publicly

available data relevant for RA of nano forms of ZnO and attempt the RA

to the extent these limited data allow.

This project specifically aimed at: 1) Clarification of how nano forms of

ZnO have been registered under REACH; 2) Analysis of the extent of data

concerning physico-chemical properties and human health hazard that have

been registered for both “bulk” (macro and micro-size particles) and “nano”

ZnO and identify data gaps; 3) Analysis of assumptions and approaches in

the RA; 4) Critical revision of those approaches in light of independently

collected scientific literature on nano-specific properties versus bulk prop-

erties in the context of toxicological effects and / or fate or exposure aspect.

The following conclusions of the project were presented:

1. Registration within REACH of ZnO is based on the dossier containing

information on different zinc compounds and different forms, bulk

and nano, and the consortium includes entities (producers or

importers) for whom any of the forms is relevant. This implies that

nano ZnO has been considered by the registrant the same substance


as bulk counterpart and registered within the same dossier. As an

example, one producer has registered nano ZnO within the

production tonnage band 100–1,000 tonnes/year/manufacture

2. 74 studies were selected and registered, as relevant for human

hazard assessment. Majority of the studies were performed in 70’s

and 80’s. Only 15 studies with exposure to nano ZnO were registered,

with the scope of endpoints limited to: inhalatory and dermal

kinetics, and acute and repeated inhalatory toxicity. Some of those

studies suffer from the lack of characterization of the nano ZnO

3. The RA within REACH registration was based on the assumption that

zinc cation (Zn2+) is the mediator of the biological activity of zinc

compounds, and the dissolution rate of Zn2+ from those compounds

will determine the activity / toxicity. The regulatory homeostatic

mechanisms for Zn2+ in humans and other organisms have been

considered efficient to limit the intake or promote excretion of Zn

during high exposure. The results of the inhalatory toxicity due to the

exposure to nano ZnO have been considered by the registrant not

relevant for the consumer exposure

a) The oral dietary supplementation of human volunteers study has

been chosen by the registrant as a critical study (NOEL 0,83 mg/kg

bw/ day) and assessment factor of 1 (no need for interspecies

extrapolation and time extrapolation considered not relevant).

Derived No Effect Levels (DNELs) for systemic effects after oral,

dermal and inhalatory exposures for consumers and workers have

been developed based on the estimated differences in the kinetics

of absorption for different routes. For dermal and inhalatory

exposures differences between solubility of different compounds

resulted in separate DNELs for soluble compounds and for

insoluble (or slightly soluble)

4. In the light of limited studies collected independently, by the

presenter, from the open sources it has been discussed within this

project: i) that the studies registered within the dossier have not

included all available and relevant studies concerning the effects of

ZnO in nano forms. Over 30 additional studies with nano ZnO were

collected with the following endpoints: dermal penetration (9

studies), tissue distribution (1 study), acute oral (3 study), acute

inhalatory (2 studies), repeated inhalatory (6 studies), mutagenicity

(8 studies), phototoxicity (1 study), other (4 studies)

a) The acute oral exposure study indicated that nano ZnO at lower

doses (1g/kg) caused changes in biochemical and enzymatic para-

meters indicating cardiovascular, hepatic and /or thrombotic ef-


fects. The relevance of those findings is not fully understood how-

ever this level meets the criteria for Specific Target Organ Toxicant

STOT (cat 2) classification (2000 ≥ C > 300 mg/kg body weight)

b) The assumption that Zn2+ is a single mediator of zinc compounds

activity may not fully cover the kinetics and mechanisms of nano

ZnO activity. Some evidence suggests that for nano structured ZnO

biological activity may not be solely based on the externally

released Zn2+. Study indicated that for toxicity in human colon

cancer cells, the direct particle – cell contact was required. Another

study on macrophage response to ZnO nanorods indicated that cell

adhesion and viability correlated to both nanotopography and

dissolved Zn2+. The regulatory homeostatic mechanism may also be

challenged due to the rapid intracellular increase of Zn2+ due to the

particle active intake and rapid intracellular dissolution

c) The relevance of the inhalatory studies on the nano ZnO cannot

be ruled out for all scenarios. The nano ZnO based products that

could potentially result in inhalatory exposure to nano ZnO are

already on the market (cosmetics: sunscreen spray, deodorant,

shaving sprays), and new type of products based on the anti-UV,

antibacterial, antifungal or water-resistance properties could

potentially result in other spray type products for treatment of

surfaces, clothes etc)

The ConsExpo modeling of inhalatory exposure to nano ZnO

following the 1 minute use of the spray application containing

25% of ZnO in a small room with middle ventilation range

resulted in high peaks of estimated concentrations in a range

of over 100 mg/m3. It was considered probable that this

value is overestimated, and experimental confirmation would

be desired. This value exceeds the Derived No Effect Level for

consumers (2.5 mg/m3) and is in a range of levels associated

with health effects in human short exposure situations. Based

on this assessment it has been recommended by the author of

this report to avoid indoors spray applications containing

high concentration of nano ZnO, before targeted and refined

RA has been performed


In conclusion this analysis reveals that the data registered for ZnO with-

in REACH is not sufficient for the RA of nano forms of ZnO. The assump-

tions used by the registrant for RA and derivation of safe limits may not

be adequate for nano ZnO. Requesting of further nano-specific data in

connection to the substance evaluation as a further process under

REACH is therefore recommended by the presenter.

6. Presentations on regulating NMs

6.1 Summary on the TG applicability and TG/GD needs (Poul Bo Larsen, Danish EPA, DK and Jukka Ahtiainen, Tukes, FI)

The presentation delivered a summary on test guideline (TG) applicability

and addressed the necessity of new TGs and Guidance Documents (GD). The

overriding issue was whether we can manage hazard and safety assessment

by using existing test guidelines or only by developing new technical guid-

ance on how to handle and characterize the exposure to NMs.

It was seen that there is no need for new TGs at the moment. Instead,

guidance documents should be developed. Exposure issues were seen

most relevant to hazard and safety assessment, broadly including sam-

ple preparation and what happens during the test-dynamic systems. The

presenters raised the issue of how to ensure and verify constant concen-

trations and challenged its desirability. The need for including new end-

points in GDs was also discussed. It was noted that as a consequence of

ageing of NMs, an underestimation of their toxicity may occur. While

case-specific guidance was seen reasonable in some cases, agreement on

the use of GDs under the MAD principle is necessary, especially when

adding optional, new endpoints for NMs.

It was argued that technical guidance should be developed for vari-

ous areas of testing, including soil studies, aquatic studies and inhalation

and skin absorption studies. While Guidance Notes on Sample Prepara-

tion and Dosimetry (GNSPD) are likely to evolve into several GDs in

many areas, there are general areas encompassing all areas of testing.

Guidance based on NM groups was also seen feasible, especially when

more knowledge on suitable groups has emerged. Grouping by uses and

activities or grouping by features, like HARN (High Aspect Ratio NMs,

are options for future guidance.

The existence of new nano-specific endpoints was emphasised. Espe-

cially in the area of physico-chemical properties, there is a need for new

TGs. For environmental fate, including degradation and accumulation,

detection remains a major issue. Understanding processes such as deg-


radation and biodegradation constitutes a further challenge. For both

ecotoxicology and human health effects, there is scope for adding new

measurements. In the case of human health, BAL in inhalation tox is a

possible new measurement.

6.2 Current regulatory views in the EU (Henrik Laursen, DG ENV, EC)

The presentation outlined key EU actions and views on the regulation of

nanomaterials. Intensification of EU action on nanomaterials is marked

by the 2004 ‘Towards a European Strategy for Nanotechnology’ Com-

munication from the Commission. Since then, the EU has taken an active-

ly communicative approach to nanomaterials, emphasising stakeholder

consultation in its actions. The European Parliament disagrees with the

Commission view that “current legislation covers risks of nanomaterials”

and concluded in a 2009 resolution that due to the lack of appropriate

data and risk assessment methods, nano risks cannot be adequately

addressed. Specific nano requirements have been considered in cosmet-

ics, food and waste regulation with mixed results – the Cosmetics Regu-

lation has proven the most successful case up to date.

Current EC tasks include the finalization of the RIPoN and the 2nd

regulatory review of nanomaterials covering all relevant legislation. The

European Parliament has also requested the Commission to evaluate the

need to review REACH, especially with reference to the need of more

simplified registration of nanomaterials with registration requirements

below the current 1 tonne per year and all nanomaterials registered as

new substances. A report on nanomaterial types and uses and safety

aspects is also soon to be made available. The report is particularly im-

portant against the speculation that rather few NMs are produced and

used in large volumes in the European market. At council request, the

report will also consider an EU nano reporting system, possibly to use

the REACH and CLP systems or a separate system. The Commission will

also be reviewing the adecuacy of nano-relevant REACH registration

dossiers for the content on health and safety information specific to na-

nomaterials. It aims to identify possible legal and technical gaps in them

and find means to rectify gaps and assess their consequences.

A nanomaterial definition is a further, notable development and is to

be adopted on the 18th of October 2011. The Draft Proposal subject to

public consultation received input from 195 stakeholders. While the

definition is based on available scientific knowledge (particularly JRC


report, SCENIHR opinion), it needs to be pragmatic to be able to deter-

mine when a material should be considered as a nanomaterial for legis-

lative and policy purposes in the EU.

In conclusion, competitiveness and innovation are fundamental to

the EU – uncertainty challenges these goals by reducing consumer de-

mand as well as by reducing supply by decreased investment. Uncertain-

ty should thus be diminished by ensuring safety, sustainability and the

application of the precautionary principle in conjuction with facts. The

ongoing legislative review aims to find out whether legislation is work-

ing for these goals.

6.3 Registrations of NMs (Marita Luotamo, ECHA)

The presentation provided discussed experiences on nanomaterials

(NMs) under REACH. According to the European Chemicals Agency (EC-

HA), in principle NMs are covered under substance definition in REACH

as either substances on their own and registered as such, or nanoforms

of a substance included in the dossier of the corresponding bulk sub-

stance. It was however noted that the REACH lacks specific require-

ments for nanomaterials.

The presentation advocated a case-by-case approach to a nanomateri-

al’s registration and safety assessment. Furthermore, registrants are en-

couraged to include information in registration and CLP dossiers. The 5.2

version of the IUCLID chemicals database includes new features enabling

registrants and notifiers to indicate nanomaterial as the form of the sub-

stance, allowing for enhanced collection of nano-specific information.

At Commission request, ECHA has undertaken inventory work on na-

nomaterials’ registration and notification with information on specified

uses. So far very few registration dossiers received have contained na-

nomaterial-specific info. In addition to participating in the RIP-oN 1, 2

and 3 work, ECHA is working on a joint nano-project with JRC including

detailed screening of information requirements provided for the identi-

fied REACH registration dossiers and making recommendations for

REACH-specific adjustments of information requirements. ECHA is also

engaged with evaluating nanomaterial-specific testing proposals and

will eventually accept or reject proposed tests, modify their conditions

and potentially request additional testing. A compliance check will then

verify compliance with information requirements and result in a formal

decision, requesting further information if necessary.


6.4 Towards harmonization of national databases for NMs on the market (Juan Pineros, MoE, BE)

Voluntary reporting systems on nanomaterials have not proven success-

ful. Harmonisation of databases is however of great importance – a joint

project by France, Italy and Belgium is working towards this goal be-

tween the three countries. While Belgium has made a nanomaterials

database compulsory starting from 2012 and the Grenelle law of 2011 is

driving a mandatory reporting scheme in France, Italy is implementing a

voluntary reporting scheme on nanomaterials, with potential to evolve

into being compulsory.

While the 2nd Environment and Health Action Plan invited the Com-

mission to evaluate the need for developing specific measures for nano-

materials relating to risk assessment and management, including the

further development of a harmonized database for nanomaterials, the

Environment Council has recently reiterated this invitation. The Com-

mission is currently assessing the added value of such a plan.

Aims and potential benefits of a common, harmonised database are

wide-ranging. Such a database would enable gathering data on the na-

nomaterials produced and sold on the market. It would also allow for

approximate estimations on occupational, consumer and environmental

exposure as well as enable traceability of nanomaterials. On a national

level, a database would help national authorities in establishing ade-

quate risk assessment and management systems. The knowledge gained

could then be used for the improvement of the legislative framework,

even at the EU level.

Comprehensiveness and links to other frameworks are seen desira-

ble while creating reporting mechanisms for nanomaterials. It was rec-

ommended that a potential harmonised database should cover all EU

legislation and have links with REACH and its risk management actions

(authorisation, restrictions). Furthermore, the database should enable

exact NM identification. Substances, mixtures, articles and consumer

products with intended release of NMs (not covered by REACH) are all

among items to be declared to the database. The obligation to declare is

borne by producers, importers, distributors, downstream users and

potentially end of life users and recyclers.

Belgium, France and Italy all employ different implementation and

enforcement tools in relation to their reporting schemes. Despite differ-

ing national arrangements, the overarching aim of the countries’ report-

ing and harmonisation endeavours is to collect data and enable tracea-

bility of NMs. While not an obstacle to market access, data collection


constitutes a first tool to react to a nano-related risk if one were to

emerge. With the lack of a harmonised EU reporting framework, cooper-

ation between member states seems to be the way forward both for the

sake of harmonisation and contribution to the discussions on improving

the legislative framework on nanomaterials.

6.5 French reporting scheme for Nanomaterials (Clarisse Durand, Ministry of Ecology, Sustainable Development, Transports and Housing, FR)

The origins and outline of the French reporting scheme for nanomateri-

als were presented via teleconference. In 2007, national brainstorming

about sustainable development was organised by the French govern-

ment. The “Grenelle de l’environnement” involved all relevant stakehold-

ers, including state and regional administration, industry, employees,

NGOs, elected representatives and scientific experts. A commitment

regarding nanomaterials was formulated expressing the need to antici-

pate the risks linked to the production and the use of manufactured na-

nomaterials (commitment n°159).

This commitment was implemented through the articles of Grenelle

Law I (2009) and Grenelle Law II (2010). In compliance with article 42

of the Grenelle Law I, a national public debate on nanotechnology was

organised between October 15th, 2009 and February 24th, 2010. The

article also gives details on the mandatory reporting scheme of nano-

materials. The quantities and uses of nanomaterials will be reported and

made available to the public and consumers. This article specifies the

need to develop a methodology for assessing risks and benefits associat-

ed with these substances and products and to improve information on

risks and protection measures. Article 185 of the Grenelle Law II details

the reporting scheme, including identity of nanomaterials and their uses,

quantities produced, imported or distributed and identity of down-

stream users. The reporting scheme aims at improving the traceability of

the nanomaterials. Some of the reported information will be made avail-

able to the public (identity of nanomaterials and their uses). The law

specifies that available data on hazards and exposures could be request-

ed by the authority. This procedure aims at gathering a minimum level

of information, it is not a risk management measure.

The conditions of execution have to be specified in a decree. The de-

cree makes a number of clarifications. The decree employs a working

definition for “substance at the nanoscale” which will be replaced when


a definition from the European Commission is available. Declarants,

including manufacturers, importers and distributors, shall report each

year. The threshold for the declaration is set at 100 grams. The decree

gives possibility to require the confidentiality of declarants’ data.

On June 23, 2011, the decree was notified in accordance with the

98/34/EC Directive. Observations from Germany, UK and the European

Commission were received. Now that the decree has been notified, it can

be forwarded to the Conseil d’Etat (highest administrative jurisdiction in

France), in order to be published by the end of the year. The reporting

scheme will start in 2013 and will relate to nanomaterials that were

produced, imported to France or distributed in 2012.

By the means of a basic report and sustainable data collection tools, it

will ensure a better market knowledge and traceability of nanomaterials in

EU market and permit a rapid and adequate response if ever a specific risk

of a nanomaterial emerges. More information on nanomaterials will also be

provided to consumers and to workers (nanomaterial identity and its uses).

However, commercially sensitive information will not be disclosed.

The mandatory reporting scheme is a French initiative, but it is un-

dertaken with other Member states, and with a willingness to contribute

to improvement of the legislative framework at the EU level.

6.6 Example(s) on NM safety assessment and RMM (Nicole Palmen, RIVM, NL)

Engineered nanoparticles and nanomaterials (ENP) are used for exam-

ple in food, coatings and electronic equipment. Workers in both industry

and research/development may be exposed to ENP. In a risk assessment,

exposure of workers to a hazardous compound (ENP) is compared with

health based occupational exposure limits (OEL). Since the body of

knowledge on ENP is limited, it is not yet possible to derive OELs for all

ENP. Due to the need to control risk, provisional nano-reference values

(P-NRV) were derived – they can be used as a pragmatic benchmark

level. In case of exposure above the P-NRV, exposure reducing measures

should be taken immediately. Since, exposure below P-NRV does not

guarantee safe working conditions, exposure-reducing measurements

should also be considered for exposures below the P-NRVs, according to

the ALARA principle (As-Low-As-Reasonably-Achievable).

Quantitative assessment of ENP was done during an electro spinning

process and downstream use in construction, car repair, painting and

paint sealant. From these measurements we learn that exposure to nano-


particles is highly dependent on the application technology. Background

exposure to nanoparticles may interfere with the measurements. Working

indoors leads to much higher ENP concentrations compared to outside

work, especially when it is windy. Real time measuring devices do not

differentiate between ENP and background, so additional sampling and

electron microscopic analysis is necessary to identify ENP. Agglomerated

nanoparticles may not be detected, which may cause an underestimation

of the exposure to nanoparticles since agglomerates may fall apart into

nanoparticles the lung. Since quantitative measurements are difficult to

perform and expensive, qualitative tools were developed to help employ-

ers and employees to perform a risk assessment. These tools are based on

the control banding principle which means that both hazard and exposure

are classified in several bands, leading to a matrix with several risk bands.

The risk bands are then coupled to risk management measures according

to the industrial hygienic strategy. Guidance for working safety- and deci-

sion matrix control (risk) levels and control measures including the train-

ing of workers are very important.

6.7 Nanotoxicology: Science at the interphases, Estonian perspective (Kaja Kasemets, National Institute of Chemical Physics and Biophysics, EE)

Engineered nanoparticles have received increasing interest in many

fields (consumer products, industry, medicine) due to their novel physi-

cochemical properties compared to the same bulk material (micro-

sized), mostly due to the remarkably increased specific surface area and

reactivity. At the same time, these changes could also be responsible for

a number of biological interactions on protein, cellular, tissue and organ

levels that could lead to toxic effects. Despite the rapidly progressing

nanotechnological research, there are remarkable knowledge gaps con-

cerning the physicochemical interactions at the nano-bio interface and

respective toxic outcome. The adequate toxicological information on NPs

is crucial to ensure successful commercialization of nanotechnology.

Since 2006, the research of the Lab in NICPB led by Dr. A. Kahru has fo-

cused on ecotoxicology of synthetic nanoparticles (NPs), mostly TiO2, ZnO

and CuO NPs. The group has been developing a combined bio-analytical

approach for the profiling of toxicological properties of metal oxide NPs.

For that, the traditional medium to high-throughout in vitro assays with

pro- and eukaryotic organisms (bacteria, yeast, algae, protozoa and crus-

taceans) have been applied comparing the NPs to their bulk counterparts,


and by evaluating the contribution of dissolved metal ions detected by

gene-modified metal-specific biosensors to the overall toxicity.

NICP research has shown that (a) ZnO and CuO NPs were toxic to

bacteria, yeast, protozoa and crustaceans, while TiO2 NPs didn’t show

any observable toxicity even at 20 000 mg/l, with the exception of algae

Pseudokirchneriella subcapitata (72-h EC50 9.7 mg/l), (b) CuO NPs

showed higher toxicity compared to their bulk counterparts, while the

ZnO NPs and bulk formulation showed comparable toxicity, (c) the ZnO

NPs (and bulk form) toxicity was caused by the dissolved Zn-ions, and

(d) CuO NPs toxicity to algae and bacteria was caused mainly by the dis-

solved ions, but to yeast Saccharomyces cerevisiae, crustaceans and pro-

tozoa Thamnocephalus platyurus, the Cu-ions didn’t explain all the toxici-

ty. We showed that the CuO NPs toxicity to yeast, protozoa and crusta-

ceans was caused also by the ROS since the oxidative stress markers as

decrease in glutathione concentration, peroxidation of cell membrane

and immune-system imbalance, respectively, was recorded.

Further research has been focused mainly on the elucidation of how

the different physical-chemical properties of metal based NPs (e.g. Ag

and Au NPs, quantum dots etc) determine their nano-bio interphases

and toxic nature using traditional (eco)toxicological and also novel gene-

modified bacterial and yeast based in vitro test systems.

7. Discussion and views on Nordic possibilities in regulating NMs

The main objective of the discussion was to discuss how Nordic

countries can build common views on OECD and EU work on

regulating nanomaterials

A panel was made up of the following participants: Henrik Laursen

(EC), Juan Pineros (BE), Peter Kearns (OECD), Poul Bo Larsen (DK)

and Jukka Ahtiainen (FI). The discussion was lead by Flemming

Ingerslev (DK). Other participants were also invited to participate in

the discussions

The conclusions of the discussion are presented below

7.1 The OECD Sponsorship Programme and its progress

There are huge expectations on the OECD testing of 13 nanomaterials for

various endpoints in order to get basic knowledge on:

what possible hazards we are facing with NMs

the applicability of existing OECD test guidelines for testing chemicals

the needs of new tests or guidance documents for using the existing TGs

The data from the ongoing explorative phase 1 for possible hazard iden-

tification is not yet completely available but we should start already

planning for phase 2, where the data produced should also be suitable

for risk assessment. The phase 2 testing should be guided by some kind

of testing strategy (or Conceptual Framework like for EDCs) which

should be developed based on the existing data.


7.2 TG and GD development

In general, the OECD guidelines are applicable for investigating the health

effects, ecotoxicity and environmental fate of nanomaterials with the im-

portant proviso that additional consideration needs to be given to the

physicochemical characteristics of the material tested, including dosing. In

some cases, there may be a need for further modification to the OECD

guidelines. Preparation of samples and dose administration are critical

considerations for the tests and therefore guidance has been developed on

sample preparation and dosimetry for the safety testing of nanomaterials.

The preliminary review of OECD-WPMN is consequently seen as a “living”

document, highlighting the feasibility of various approaches and allowing

for continuous updates, given the rapid developments in this area.

There was a consensus that only very few possible new nanospecific

endpoints (measured variables) are needed for the NMs to be added to

the Test Guidelines or developed as new Test Guidelines. These new

nanospecific needs are mainly in the area of physico-chemical character-

ization. However, some of the endpoints in existing Test Guidelines are

more nanorelevant than others, for example BAL (bronchious alveolar

lavage) in inhalation toxicity testing. In the area of ecotoxicity most of

the existing endpoints are also nanorelevant and in the area of environ-

mental fate testing the detection and characterization of NMs in the en-

vironmental media or in tissues is the challenge.

7.3 REACH implementation

The information submitted in the registration dossier for a nanomateri-

al, as part of the bulk registration or on its own, needs to comply with

the information requirements and, if relevant, the CSR requirements for

all the registrant’s identified uses of the nanomaterial.

There is no one-size-fits-all solution to treating nanomaterials as forms

of a bulk substance or a separate substance. Further practice needs to

evolve on developing rules on how size should be used as a characterizer

and when could it be used as an identifier. The Nordic countries may have

differing views on whether NMs should be always registered as substances of

their own and considered as new substances. However, if this were to be the

case, the data requirements based on tonnages should be reconsidered.

If specific substance identification rules for nanomaterials are devel-

oped, they must be consistent with practices for substances in general.

Such rules need to maintain a certain degree of flexibility to allow use of


the most practical solutions, provided that the information is relevant

and complete for all forms of the substance, and that safe use is ensured.

REACH obliges the registrant to ensure that his registration(s) demon-

strate(s) that all forms of the substance in his dossier(s) can be used safe-

ly. The question of substance identity is not critical in this regard. The

focus of attention should therefore be on ensuring that the submitted data

are applicable or appropriate for the all form(s) covered in a dossier(s) in

question and on ensuring that the registrant has provided all relevant

information to allow the safe use of the substance by the downstream

users and consumers. However, there are concerns amongst the Nordic

countries whether industry would comply with this properly. Only 3 regis-

trants out of 46 with NM use of the same substance had indicated the nano-

material use in IUCLID at the first registration in 2010.

Standard information requirements, as described in the Annexes VII

– XI, apply equally to nanoforms and bulkforms. The registrant has to

make sure that in case tests are performed, these must be representa-

tive of the form(s) of the registered substance. Alternatively when any

kind of read-across (with safety factors) is used between the forms, the

registrant has to make sure that this is scientifically justified. However,

it was concluded that nano-specific data requirements would need new

tonnage triggers and data requirements. This would also be the need for

a common registration.

ECHA has now been invited to further assess the relevant submitted

dossiers in a “bottom-up” process to build up more knowledge and ex-

perience on substance identification in the registration of nanomaterials.

If appropriate, ECHA should use this experience to develop further prac-

tical rules in co-operation with the European Commission, Member

States and stakeholders. Such a bottom-up process should significantly

contribute to a better understanding on how nanomaterials should be

treated within the REACH framework.

This could be perhaps supported by Nordic countries as an interim so-

lution. However, the revised ECHA Guidance on registration should make

explicit, that the registrants and SIEF should address and assess also all

the relevant uses of NMs of that particular substance. This demand should

be very visible and clear probably under the title “What to register”.

It was also proposed that if a member state’s regulators have doubts

that the safety assessment of a NM form is not adequate, these substances

(e.g. the case of ZnO; having the nanoform in the market) could be raised

into the CORAP process by a member state.

It was also discussed whether a separate regulation for nanomaterials

would be more appropriate, in order not to make changes within REACH.


Based on the experiences in the RIP-oNs and the experiences from the

OECD sponsorship programme, a future task for Nordic cooperation could

be to start work on examining specific triggers for data requirement and a

testing strategy for nanomaterials.

7.4 NM product labelling and registers

There was a consensus that ideas on possible product registers for

products containing NMs could be supported for traceability of NMs

through their life-cycle. However, we should be able to make best use of

our existing product registers in the Nordic countries. Furthermore, the

register system should be complementary and not amount to duplica-

tion of REACH registration.

The idea of product labelling could also be supported for consumer

transparency and giving the freedom of choice to the consumer. This

would then also require better communication for society to gain an

understanding of what this kind of labelling means.

7.5 Establishing a Nordic Regulatory NM network

The idea of strengthening Nordic cooperation in the field of nanosafety

was supported. This should bring together research groups and regula-

tors. Regulatory views could thus be better discussed and coordinated if

needed. The core of this nano-group should also coordinate NM related

work in all NKG groups.

If Nordic countries have reason to doubt the adequacy of NM safety

assessment in registration and one of the countries would take this to

the CORAP-process for substance evaluation, there should be strong

Nordic back-up and resources for this process.

Starting a TG/GD project in the OECD test guideline programme was

discussed as a concrete idea for future regulatory cooperation. The

meeting identified two possible fields where there is need for work and

Nordic scientific capacity. For ecotoxicology, the development of Guid-

ance Document(s) for soil and sediment toxicity could be such an area.

In the human health area, the knowledge on genotoxicity assessment

could be clearly identified. One possibility is to get involved with the

development of a Comet assay for an OECD TG, and ensure that it would

also become applicable for NM testing as well as for general chemicals.

Sammanfattning och slutsatser

Konferensen The Nordic NanoNet Workshop and EDC diskussion ordna-

des som en del av Finlands ordförandeskap för Nordiska ministerrådet

(NMR) 2011. Konferensen ordnades av Säkerhets- och kemikalieverket

(Tukes) i Finland och ägde rum 11–13 oktober 2011 på Hanaholmens

kongresscenter i Esbo, Finland. Huvudtema för konferensen var säker-

hetsbedömning och hantering av nanomaterial (NM). Dessutom ordna-

des parallellt en endagskonferens som tillägnades kriterier för endo-

krinstörande kemikalier (EDC). Organisatörerna är tacksamma för att

Nordiska ministerrådet tillhandahöll resurser för mötet.

Konferensens huvudsakliga teman var följande:

Regelverk och sambanden mellan NM och EDC

Tillämpbarhet av riktlinjerna för testning och

riskbedömningsmetodik för nanomaterial

Möjligheter till regelverk för EDC och NM

Regelverk om NM

Utveckling av EDC-kriterier

Framtida nordiskt samarbete kring regelverket

Regelverk och sambanden mellan NM och EDC

Jukka Ahtiainen (Tukes, FI) gav en inledande presentation av regelverket

och sambanden mellan EDC och NM, och presenterade några av konferen-

sens huvudteman och målsättningar. Henrik Tyle (Danish EPA, DK) talade

i Pia Juul Nielsens ställe och använde Danish Endocrine Network som ett

exempel på ett nätverk för lagstiftningsåtgärder som har förbättrat sam-

förståndet mellan lagstiftare och vetenskapsmän. Petteri Talasniemi (Tu-

kes, FI) presenterade OECD:s reviderade begreppsram (Conceptual

Framework, CF) och poängterade att begränsningarna i vägledningen

härrör från två källor: antingen är erfarenheten av användningen av ifrå-

gavarande metod otillräcklig eller så tillför metoden inga betydande för-

delar i förhållande till befintliga studier. Henrik Tyle förespråkade i sin

presentation av OECD:s reviderade CF och utkast till vägledningsdoku-

ment (Guidance Document, GD) en fallspecifik utgångspunkt i bedöm-

ningen av kemikalier som beaktar all tillgänglig information.


Emma Vikstad (Kemi, SE) betonade det överhängande behovet av en

definition av nanomaterial som omfattar all ”nanorelevant” lagstiftning

inom EU. Poul Bo Larsen (Danish EPA, DK) poängterade att det krävs

mycket arbete för att inkorporera nanomaterial i REACH och föreslog att

separata och mer flexibla bestämmelser för nanomaterial parallellt med

REACH eventuellt kunde vara en lämplig lösning.

Den första konferensdagen avslutades med diskussioner om regel-

verket och sambanden mellan EDC och NM i utbrytargrupper. Slutsat-

serna presenteras nedan.

Gå vidare med beslut eller vänta på mer vetenskaplig information?

Den ståndpunkt som fick mest understöd var att inte vänta på mer ve-

tenskaplig information utan gå vidare med beslut och vägledning. Den

höga osäkerheten kring och bristen på klarhet i hurdan information som

behövs om nanoteknik förstärker viljan till snabba beslutsåtgärder.

Inom EDC är grunden för bestämmelser och kunskapen bättre.

Definitionen av nanomaterial

Alla grupper ansåg att det finns ett överhängande behov av en definition

av nanomaterial för att reglerande åtgärder ska vara möjliga. En prak-

tisk strategi föredrogs i det rådande osäkra läget. Man enades emellertid

om att den vetenskapliga grunden borde inkorporeras i denna praktiska

strategi. Grupper var också överens om att det finns ett behov av en de-

finition av EDC och kriterier som omfattar alla hormonstörningar.

REACH – EDC, NM och lagstiftning

Även om man inte uppnådde enighet i frågan om hur REACH-

förordningen skulle kunna garantera säkerheten hos NM, enades delta-

garna om att ytterligare åtgärder för att garantera säkerheten behövs.

Potentiella metoder för att garantera att NM behandlas separat från

bulkmaterial inbegriper ändringar av lagstiftningen, nya reviderade

tillägg eller adekvat vägledning från ECHA för registrering. Man ansåg

att en ny bilaga om EDC-kriterier, som liknar den om PBT-kriterier, an-

tagligen behövs för att identifiera EDC under REACH.

Registrering av NM

Den allmänna opinionen var att det vore säkrare att kategoriskt regi-

strera NM som nya ämnen med nanoanpassade informationskrav. Andra

lämpliga metoder, såsom bättre vägledning för registrering från ECHA,

fick emellertid också understöd.


Den befintliga lagstiftningens tillräcklighet för reglering av EDC

De befintliga verktygen ansågs i allmänhet tillräckliga för att reglera

bekräftade EDC. De kombinerade följderna av EDC från olika källor an-

sågs emellertid vara svåra att behandla i tillräcklig grad enligt den gäl-

lande lagstiftningen.

Tillämpbarhet av riktlinjerna för testning och riskbedömningsmetodik för nanomaterial

Under den andra konferensdagen låg fokus på tillämpbarheten av rikt-

linjerna för testning (test guidelines, TG) och riskbedömningsmetoder

(risk assesment, RA) för nanomaterial. Peter Kearns (OECD, EHS/ENV)

gav en överblick av OECD:s arbete inom NM och uttalade sig närmare

om förhållandet mellan principerna för god laboratoriesed och ömsesi-

digt godkännande av uppgifter i förhållande till riktlinjerna för testning

och framtagningen av vägledningsdokument. Jukka Ahtiainen samman-

fattade möjligheterna för vidareutveckling av testpraxisen: en möjlighet

är att skapa en begreppsram för att testa och bedöma NM som liknar

begreppsramen för EDC. Sjur Andersen (KLIF, NO) presenterade OECD:s

sponsorprogram (Sponsorship Programme) samt förklarade testernas

omfattning och introducerade de berörda sponsorerna. Janneck Scott-

Fordsmand (DMU, DK) uttalade sig om det nordiska nanosilvrets bidrag

till sponsorprogrammet och diskuterade några av utmaningarna vid

testningen, vilket utlöste en het diskussion.

Erik Joner (Bioforsk, NO) och Deborah Oughton (Universitetet for

miljø- og biovitenskap, NO) presenterade tillsammans studier om NM:s

miljöeffekter: tester i relevanta jordtillstånd inklusive åldrande ansågs

vara viktigt, såsom också möjligheterna att använda neutroner för att

upptäcka NM i metall. Geert Cornelis (Göteborgs universitet, SE) inrik-

tade sig på upptäckten av NM i miljön och frågor kring uppföljning av

exponering – fältflödesfraktionering (FFF) kombinerat med induktivt

kopplad plasma masspektrometri (ICP-MS) och single particle ICP-MS

(SP-ICP-MS) föreslogs för känslig analys av syntetiska nanopartiklar i

komplexa miljöer.

Marit Låg (Nasjonalt folkehelseinstitutt, NO) sammanfattade i sin pre-

sentation av inandning av nanopartiklar att syntetiska nanopartiklar har

potential att förklara hälsoeffekter; toxiciteten beror på exponeringen för

dessa partiklar. Julia Catalán (FIOH, FI) talade om testning av genotoxicitet

i NM och dess utmaningar – man vet t.ex. sällan hur stor del av nano-

materialet som absorberas av cellerna och huruvida skillnader i intracel-

lulära kanaler kan förklara skillnader i genotoxicitet. Lise Fjellsbø (NILU,


NO) talade om in vitro-studier inom NM-testning och berättade om erfa-

renheter från projektet NanoTEST som analyserar hur nanopartiklar ab-

sorberas av och transporteras genom biologiska barriärer. I dagens sista

presentation talade Jussi Kukkonen (Itä-Suomen yliopisto, FI) om effek-

terna i vattendrag och ödet för nanomaterial i nordisk miljö.

Diskussionen kring tillämpbarheten fortsatte i mindre grupper, dis-

kussionernas slutsatser presenteras nedan.

Befintliga riktlinjer för testning och ny vägledning

Grupper enades om att utveckling av ytterligare riktlinjer är nödvändigt

men de befintliga riktlinjerna är en bra utgångspunkt för säkerhets- och

riskbedömningen av nanomaterial. Man erkände att det finns tekniska

och begreppsmässiga utmaningar i de befintliga riktlinjerna. Alla grup-

per betonade behovet av flexibilitet i vägledningen.

Vägledning för specifika testområden och vägledning som baserar

sig på NM-grupper

Olika vägledning för olika testområden ansågs nödvändigt. Det är fortfa-

rande svårt att gruppera nanomaterial i praktiken. Man ansåg ändå att

om dessa praktiska hinder i grupperingen kunde överkommas skulle det

vara en bra grund för vägledningen.

Möjligheter till regelverk för EDC och NM

Konferensens tredje dag inleddes med ett möte om möjligheterna till

regelverk för EDC och NM. Sofie Christiansen, Pia Juul Nielsen och Rikke

Holmberg (Danish EPA, DK) presenterade resultatet från tre nordiska

EDC-workshoppar angående kriterier, kombinerade påföljder och dis-

positiva regleringsåtgärder som ordnades i Köpenhamn hösten 2010.

Rikke Holmberg informerade också om i vilket skede EU:s lagstiftnings-

arbete angående EDC, kombinerade effekter och NM befinner sig. Ka-

tarzyna Malkiewicz (Kemi, SE) avslutade mötet med en presentation av

registreringen av zinkoxid i REACH och rekommenderade att begära

ytterligare nanospecifika uppgifter i anslutning till materialutvärdering-

en i REACH. Representanter för danska EPA höll ett separat möte om

utvecklingen av EDC-kriterier, parallellt med ett möte om regelverket

kring nanomaterial.


Lagstiftning om NM

Vid öppnandet av mötet om regelverket kring nanomaterial betonade Poul

Bo Larsen (Danish EPA, DK) och Jukka Ahtiainen (Tukes, FI) uppkomsten av

nya nanospecifika effektmått (endpoints) och behovet av att ta fram väg-

ledning och nya riktlinjer för testning inom fysisk-kemiska egenskaper.

Henrik Laursen (DG ENV, EC) gav en överblick av EU:s viktigaste åt-

gärder och synpunkter på regelverket kring NM; syftet med den på-

gående överblicken av lagstiftningen är att fastställa huruvida den gäl-

lande lagstiftningen garanterar säkerhet och hållbarhet samt konkur-

rens och nytänkande. Marita Luotamo (ECHA) talade om erfarenheterna

av NM och framtida utveckling under REACH: en fallspecifik strategi för

registreringen av nanomaterial föredrogs.

Juan Piñeros (MoE, BE) tog upp harmonisering av nationella NM-

databaser på marknaden: till fördelarna hör möjligheten till insamling av

data och uppskattning av exponering, riskbedömning och -

hanteringssystem samt förbättring av lagstiftningen. Clarisse Durand

(Ministry of Ecology, Sustainable Development, Transport and Housing,

FR) behandlade mer detaljerat initiativet till det obligatoriska franska

rapporteringsschemat som inletts i samarbete med Belgien och Italien.

Nicole Palmen (RIVM, NL) presenterade exempel på säkerhetsbe-

dömningen av NM, i synnerhet med tanke på exponering för syntetiska

nanopartiklar i arbetet. Kaja Kasemets (NICPB, EE) stod för den sista

presentationen och diskuterade forskningen kring ekotoxiciteten hos

syntetiska nanopartiklar vid NICPB.

Diskussion om nordiskt samarbete kring regelverket för NM

Konferensen Nordic NanoNet Workshop avslutades med en diskussion

kring det nordiska samarbetet inom EU och OECD. Slutsatserna av denna

diskussion som är avsedda för lagstiftare presenteras nedan.

OECD:s sponsorprogram och dess utveckling

Förväntningarna på OECD:s testning av 13 nanomaterial för olika ef-

fektmått är mycket stora. Materialet från den pågående explorativa fa-

sen 1 för identifiering av eventuella faror är ännu inte helt tillgängligt,

men vi borde redan börja planera fas 2, där data som uppkommer borde

vara lämplig för riskbedömning. Testningen i fas 2 borde vägledas av en

sorts teststrategi eller begreppsram, såsom för EDC, som utvecklas uti-

från befintlig data.


Utveckling av TG och GD

I princip kan OECD:s riktlinjer tillämpas på undersökning av hälsoeffek-

ter, ecotoxicitet och miljöeffekter av nanomaterial men det är viktigt att

även beakta det testade materialets fysikalisk-kemiska egenskaper. I

vissa fall kan det finnas ett behov av ytterligare ändringar av OECD:s

riktlinjer. Provberedningen och doseringen är ytterst viktiga i testerna

och därför har man tagit fram ett vägledningsdokument för provbered-

ning och dosimetri som tillämpas på säkerhetstestning av nanomaterial.

Med tanke på den snabba utvecklingen i området har OECD-WPMN:s

inledande utkast ansetts vara ett ”levande” dokument som betonar olika

metoders genomförbarhet och tillåter kontinuerliga uppdateringar.

Man enades om att väldigt få potentiella nya nanospecifika effektmått

behöver läggas till riktlinjerna för testning eller tas fram som nya riktlin-

jer. Dessa nya nanospecifika behov berör främst området fysikalisk-

kemisk karakterisering. Vissa av effektmåtten i de befintliga riktlinjerna

för testning är mer ”nanorelevanta” än andra. Inom ekotoxicitet är de

flesta befintliga effektmåtten också ”nanorelevanta”. Inom miljöeffekter

utgörs utmaningen i testningen av identifiering och karakterisering av

NM i miljö eller vävnad.

Implementering av REACH

Informationen i registreringsunderlaget för ett nanomaterial, som en del

av bulkregistrering eller individuellt, måste överensstämma med in-

formationskraven och vid behov med CSR-kraven för registrantens alla

identifierade användningssyften för nanomaterial.

Det finns ingen lösning av typen one-size-fits-all i behandlingen av

nanomaterial som bulksubstans eller en separat substans. Vidare test-

ning måste fokusera på att ta fram regler för hur storleken ska användas

som ett särdrag och när den ska användas som en identifierare. De nor-

diska länderna har eventuellt skilda åsikter om huruvida NM alltid ska

registreras som separata substanser och behandlas som nya substanser.

Om det senare skulle gälla borde informationskrav styrda av tonnage

eventuellt tänkas över igen.

Om specifika regler för identifiering av nanomaterialets substans ut-

vecklas måste de överensstämma med den allmänna praxisen för sub-

stanser. Sådana regler måste ha en viss flexibilitet för att tillåta tillämp-

ning av de mest praktiska lösningarna, förutsett att informationen är

relevant och fullständig för alla former av substansen och att säker an-

vändning garanterats.

REACH kräver att registranten säkerställer att hans registrering(ar)

visar att alla former av substansen i underlaget kan användas på ett sä-

kert sätt. Substansens identitet är inte viktig i detta avseende. Fokus


borde därför riktas mot att säkerställa att uppgifterna kan tillämpas och

gäller för alla former i underlaget i fråga, samt att säkerställa att re-

gistranten har lämnat all relevant information för att nedströmsanvän-

dare och konsumenter kan använda substansen på ett säkert sätt. Det

finns emellertid oro bland de nordiska länderna om huruvida industrin

följer detta på rätt sätt. Endast 3 av 46 registranter som använt NM med

samma substanser hade meddelat om användningen av nanomaterial i

IUCLID i samband med den första registreringen 2010.

Standardkraven på information, såsom förklaras i bilagorna VII–XI,

gäller lika för nanoformer och bulkformer. Om tester utförs måste re-

gistranten säkerställa att testerna representerar den registrerade sub-

stansens form(er). Man sammanfattade att kraven på nanospecifik data

skulle behöva nya ”tonnage triggers” och datakrav. Detta skulle också

medföra ett behov av gemensam registrering.

ECHA har bjudits in till att vidareutvärdera underlagen i en bottom-

up-process för att få mer kunskap om och erfarenhet av att identifiera

substanser vid registreringen av nanomaterial. I tillämpliga fall borde

ECHA använda denna erfarenhet till att ta fram ytterligare praktiskta

regler i samarbete med Euroepiska kommissionen, medlemsstaterna och

intressenter. En dylik bottom-up-process torde bidra betydligt till en

bättre förståelse av hur nanomaterial ska behandlas inom REACH-

ramen. De nordiska länderna stöder eventuellt detta som en tillfällig lös-

ning. ECHA:s reviderade vägledningsdokument om registrering borde

emellertid klargöra att registranterna och SIEF ska föra fram och bedöma

all relevant användning av NM i substansen i fråga. Detta krav ska vara

mycket tydligt och klart, förslagsvis under rubriken ”Vad ska registreras.”

Man föreslog också att om en medlemsstats lagstiftare oroar sig för att

säkerhetsbedömningen av en NM-form är otillräcklig ska dessa substanser

(t.ex. fallet ZnO som har en nanoform på marknaden) kunna föras till

CORAP-processen av en medlemsstat.

Man diskuterade också huruvida ett separat regelverk för nanomateri-

al skulle vara mer lämpligt för att undvika ändringar inom REACH. På

basis av erfarenheterna från RIP-oNs och OECD:s sponsorprogram kunde

ett framtida nordiskt samarbete bestå av att studera specifika triggers för

datakrav och en teststrategi för nanomaterial.


Skapande av ett nordiskt regelverk för NM

Att stärka det nordiska samarbetet inom nanosäkerhet understöddes.

Detta torde föra samman forskningsgrupper och lagstiftare. Synpunkter

om lagstiftningen kan på så sätt diskuteras och koordineras bättre. Kär-

nan i denna nanogrupp skulle alltså koordinera arbete i anslutning till

NM i alla NKG-grupper.

Om de nordiska länderna har orsak att tvivla på tillräckligheten av

säkerhetsbedömningen av NM vid registreringen, och ett av länderna för

ärendet till CORAP-processen för utvärdering av substansen ska de nor-

diska länderna stötta processen och bidra med resurser.

Inledandet av ett TG/GD-projekt i OECD:s program för riktlinjer för

testning diskuterades som en konkret idé för framtida samarbete inom

lagstiftning. Under mötet identifierades två möjliga områden där det

finns behov av arbete och nordisk vetenskap. Inom ekotoxikologi är

framtagningen av vägledningsdokument för toxicitet i jord och sediment

ett sådant område. Vad gäller människans hälsa kunde kunskap inom

bedömningen av genotoxicitet identifieras tydligt. En möjlighet är att

engagera sig i utvecklingen av en ”Comet assay” för en OECD TG och

säkerställa att den också kan tillämpas på NM-testning så väl som på

allmänna kemikalier.

Abbreviations

ADME Adsoptrion Distribution Metabolism and Excretion

ALARA As-low-as-reasonably-achievable

ATP Admendment to Technical Process (REACH & CLP)

BAL Bronchious alveoli lavage

BfR Federal Institute for Risk Assessment (Germany)

CARACAL Competent Authorities for REACH and CLP

CASGnano CARACAL sub-group on nanomaterials

cFFF Centrifucal Field Flow Fractionation

CLP Classification, Labelling and Packaging

CMR Carcinogenic, Mutagenic or Toxic to Reproduction (Hazard classification)

COPD Chronic Obstructive Pulmonary Disease

CORAP Community Rolling Action Plan (REACH)

CSR Chemical Safety Report (REACH)

DIT Developmental Immutoxicity

DNEL Derived No-Effect Level

DNT Developmental Neurotoxicity

ED Endocrine Disruptor or Endocrine Disruption

EDC Endocrine Disrupting Chemical

EDTA AG Endocrine Disrupters Testing and Assessment Advisory Group

EHS Environmental Health and Safety

ENP Engineered nanoparticle

ENV Environmental

EOGRTS Extended One Generation Reproduction Toxicity Study

ERA Environmental Risk Assessment

EU MS EU Member State

EU TM EU Test Method

FFF Field Flow Fractionation

FFLCT Fish Full Life-cycle Test

FSA Fish Screening Assay

FSDT Fish Sexual Development Test

FSTRA Fish Short-Term Reproduction Assay

GHS Globally Harmonized System for Classicication and Labelling

GLP Good Laboratory Practise (OECD)

GNSPD Guidance Notes for Sample Preparation and Dosimetry (OECD)

HARN High Aspect Ratio Nanomaterial

HPVC High Production Volume Chemicals

ICP-MS Inductively Coupled Plasma-Mass Spectrometry

IPCS International Programme on Chemical Safety

IUCLID International Uniform Chemical Information Database

MAD Mutual Acceptance of Data (OECD)

MMGT Medaka Multigeneration test

MS Member State

MSC Member State Committee (ECHA)

MW Molecular Weight

NGO Non-Governmental Organisation

NM Nanomaterial

NOAEL No Observed Adverse Effect Level

NOEC No Observed Effect Concentration, Lowest Observed Effect Concentration

NOEL No Observed Effect Level, Lowest Observed Effect Level

nZVI nano-Zero Valent Iron

OECD CF OECD Conceptual Framwork for endocrine disrupters testing

OECD GD OECD Guidance Document

OECD GD 140 Androgenized Stickleback Screening assay

OECD TG OECD Test Guideline

OECD WPMN OECD Working Party on Manufactured Nanomaterials


OECD TG 206 Avian Reproduction Test

OECD TG 211 Daphnia magna Reproduction Test

OECD TG 218, 219 Chrironomid Reproduction Test

OECD TG 222 Earthworm reproduction test

OECD TG 225 Lembriculus sediment worm toxicity test

OECD TG 229 Fish Short Term Fish Screening Assay

OECD TG 230 21-day Fish Assay

OECD TG 231 Amphibian Metamorphosis Assay

OECD TG234 Fish Sexual Development Test

OECD TG 407 Repeated Dose 28-day Oral Toxicity Study in Rodents

OECD TG 415 One-Generation Reproduction Toxicity Study

OECD TG 416 Two-Generation Reproduction Toxicity

OECD TG 440 Uterotrophic assay

OECD TG 441 Herschberger assay

OECD TG 443 Extended on generation reproductive toxicity study (EORGTS)

OEL Occupational exposure Limit

PBT Persistent, Bioaccumulative and Toxic

PM Particulate Matter

PNEC Predicted No-Effect Concentration

P-NRV Provisional nanoreference value

PPP Plant Protection Product

PVA Poly vinyl acetate

QSAR Quantitative Structure Activity Relationship

RA Risk Assessment

REACH Regulation (EC) no 1907/2006 on Registration, Authorisation and Restriction of Chemicals

RIPoN REACH Implementation Project on nanomaterials

ROS Reactive Oxygen Species

SCENIHR Scientific Committee for Emerging and Newly Identified Health and Environmental Risks

SEM Scanning Electron Microscope

SNUR Significant New Use Rule (USEPA)

SP-ICP-MS Single Particle Inductively Coupled Plasma- Mass Spectrometry

STOT Specific Target Organ Toxicant

TEM Transmission Electron Microscope

TGD Technical Guidance Document

TRISK European Toxicology Risk Assessment Training

WoE Weight of Evidence

Appendix A: Programme

Nordic NanoNet Workshop for researchers and regulators on safety

evaluation of nanomaterials and Nordic discussion on EDC criteria

Hanasaari Congress Centre, Espoo, Finland

Tuesday 11.10.2011

11:00 Arrival and registration of participants

12:00 Lunch

Regulatory framework and linking the EDC and NM issues

(chair: Marilla Lahtinen, Ministry of Social Affairs and Health, FI)

13:00 Opening (Pekka Jalkanen, Ministry of the Environment, FI)

13.15 Introduction: technical challenges and policy issues (Jukka Ahtiainen, Tukes, FI)

13.30 Introduction: networks as a tool for regulatory actions (example: The Danish Endocrine

Network) (Henrik Tyle, Danish EPA, DK)

13.45 Introduction: The OECD Conceptual Framework on Endocrine Disrupters (Petteri

Talasniemi, Tukes, FI)

14.00 Introduction: The OECD Guidance Document on Standardised Test Guidelines for

Evaluating Chemicals for Endocrine Disruption (Henrik Tyle, Danish EPA, DK)

14:30 Introduction: NM definition and substance identification (Emma Vikstad, Kemi, SE)

14.45 Introduction: Implementing REACH on NMs: EU guidance on NM safety assessment

(Poul Bo Larsen, Danish EPA, DK)

15:00 Coffee and gradually in to the discussions

15:15 Four break-out groups addressing pre-handed questions

16:30–17:30 Wrapping up the groups and discussion

17:30–19:30 Optional outdoors activities, sauna and swimming

19:30 Dinner


Wednesday 12.10.2011

Test guidelines and their applicability to assess NMs

(chair: Ivar Lundbergh, Kemi, SE)

9:00 What TG tools we have, and which TGs and GDs have to be developed for NM testing

(Peter Kearns, OECD EHS/ENV)

9:30 Addressing the data requirements for the safety assessment of NMs under REACH (Juan

Riego Sintes, JRC Ispra, EC)

10.00 OECD Sponsorship Programme and NM testing (Sjur Andersen, KLIF, NO)

10:15 Nordic nanoAg contribution to the Sponsorship Programme (Janneck Scott-Fordsmand,

DMU, DK)

10:45 Environmental fate studies on NMs (Erik Joner, Bioforsk, NO and Deborah Oughton,

Norwegian University of Life Sciences, NO)

11.15 Coffee

11:45 Detection of NMs in the environment and verification of exposure (Geert Cornelis,

University of Gothenburg, SE)

12:15 Inhalation of nanoparticles and health effects (Marit Låg, Norwegian Institute of Public

Health, NO)

12:45 Discussion

13:00 Lunch

(chair: Yvonne Andersson, Kemi, SE)

14.00 Update on genotoxicity of NMs (Julia Catalán, FIOH, FI)

14:30 In vitro studies in NM testing – Experience from NanoTEST (Lise Fjellsbø, NILU, NO)

15:00 Aquatic effects and fate of nanomaterials in the Nordic environment (Jussi Kukkonen,

University of Eastern Finland, FI)

15:30 Coffee and break-out groups (4) on applicability of TGs and testing

2 ecotox (moderators, rapporteurs)

2 tox (moderators, rapporteurs)

16:30 Wrapping up and discussion

17:00 End of the day

17:00–19:30 Optional outdoors activities, sauna and swimming

19.30 Dinner


Thursday 13.10.2011

A common session on linking the EDC and NM issues followed by two parallel sessions for nanomaterial testing and assessment and for EDC criteria

Common session

(chair: Henrik Tyle, Danish EPA, DK)

8:15 Outcome of the three Nordic workshops on EDCs held in Denmark in the autumn 2010

(Combined effects, Criteria and Soft Regulatory Measures) (Sofie Christiansen DTU and

Pia Juul Nielsen, Danish EPA, DK)

8.45 Regulation of combined effects – status of the EU work (Rikke Holmberg, Danish EPA, DK)

9.15 Registration of ZnO in REACH – is it sufficient for safety evaluation of nano ZnO

(Katarzyna Malkiewicz, Kemi, SE)

Session on EDC criteria

(chair: Pia Juul Nielsen, Danish EPA, DK)

10.00–10.30 Establishment of the Danish proposal for criteria and options for regulation of endocrine

disruptors under REACH (Pia Juul Nielsen, Danish EPA)

10.30–10.45 Coffee break

10.45–11.15 Revised OECD conceptual framework for endocrine disruptors and introduction to the

OECD Guidance Document on Standardised Test Guidelines for Evaluating Chemicals for

Endocrine Disruption (Henrik Tyle, Danish EPA (ENV) and Sofie Christiansen (HH),

Division of Toxicology and Risk Assessment, National Food Institute, Technical University

of Denmark)

11.15–12.00 Science based criteria for endocrine disruptors developed by the Danish centre on

Endocrine Disrupters (Sofie Christiansen, Division of Toxicology and Risk Assessment,

National Food Institute, Technical University of Denmark and Henrik Holbech, Institute

of Biology, University of Southern Denmark)

12.00–13.00 Lunch

13.00–13.30 Criteria for endocrine disrupters – central discussion points (Marie Louise Holmer,

Danish EPA)

13.30–15.00 Break out discussions in small groups of approximately 6 participants per group

(questions for discussion will be handed out in the beginning of the day)

15.00–15.45 Reports from the break out groups and short overview of the outcome of the day

15:45 Discussion and conclusions

16:00 End of the workshop

Session on regulating NMs

9:30 Summary on the TG applicability and TG/GD needs (Poul Bo Larsen, Danish EPA, DK and

Jukka Ahtiainen, Tukes, FI)

10:00 Current regulatory (REACH) views in EU (Henrik Laursen, DG ENV, EC)

10:30 Registrations of NMs (Marita Luotamo, ECHA)

11:00 Coffee

11:30 NMs in products: labelling and product registers (Juan Pineros, MoE, BE / Clarisse

Durand, Ministry of Ecology, sustainable Development, Transports and Housing, FR)

12:00 Example(s) on NM safety assessment and RMM (Nicole Palmen, RIVM, NL)

12:30 Nanotoxicology: Science at the interphases, Estonian perspective (Kaja Kasemets,

National Institute of Chemical Physics and Biophysics, EE)

13.00 Lunch and room check-out


14:00 Discussion mainly for the regulators:

(chair: Flemming Ingerslev, Danish EPA, DK)

Can we build common views on the OECD and EU work? Discussion lead by the chair and a panel on the issues

OECD Sponsorship Programme and its progress

TG and GD development

REACH implementation (substance ID, data requirements, risk assessment and risk

management)

NM product labelling and registers

14:30 Establishing a Nordic Regulatory NM network

to coordinate NM related work in NKG groups

to start TG/GD project in the OECD test guideline programme

15:30 Discussion and conclusions

16:00 End of the workshop

Appendix B: Presentations

PowerPoint slides for selected Nordic NanoNet Workshop presentations,

made available by their authors, can be accessed at the following address:

http://www.tukes.fi/nanoturvallisuus

http://www.tukes.fi/nanoturvallisuus

Appendix C: List of Participants

Denmark Anna-Maria Andersson Centre on Endocrine Disrupters, Copenhagen University Hospital

Poul Bo Larsen Danish Environmental Protection Agency (MST)

Berit Hallam Danish Environmental Protection Agency (MST)

Rikke Holmberg Danish Environmental Protection Agency (MST)

Marie Louise Holmer Danish Environmental Protection Agency (MST)

Flemming Ingerslev Danish Environmental Protection Agency (MST)

Pia Juul Nielsen Danish Environmental Protection Agency (MST)

Henrik Tyle Danish Environmental Protection Agency (MST)

Henrik Holbech Institute of Biology, University of Southern Denmark (SDU)

Janneck Scott-Fordsman National Environmental Research Centre (DMU), Aarhuus University

Sofie Christiansen National Food Institute, Technical University of Denmark (DTU)

Finland Markus Sillanpää Finnish Environment Institute (SYKE)

Helena Valve Finnish Environment Institute (SYKE)

Anja Hallikainen Finnish Food Safety Authority (Evira)

Julia Catalan Finnish Institute of Occupational Health (TTL)

Sirpa Huuskonen Finnish Institute of Occupational Health (TTL)

Helene Stockmann-Juvala Finnish Institute of Occupational Health (TTL)

Virpi Väänänen Finnish Institute of Occupational Health (TTL)

Jukka Ahtiainen Finnish Safety and Chemicals Agency (Tukes)

Annette Ekman Finnish Safety and Chemicals Agency (Tukes)

Elina Ekokoski Finnish Safety and Chemicals Agency (Tukes)

Päivi Karnani Finnish Safety and Chemicals Agency (Tukes)

Susan Londesborough Finnish Safety and Chemicals Agency (Tukes)

Selma Mahiout Finnish Safety and Chemicals Agency (Tukes)

Leona Mattsoff Finnish Safety and Chemicals Agency (Tukes)

Kirsi Myöhänen Finnish Safety and Chemicals Agency (Tukes)

Hinni Papponen Finnish Safety and Chemicals Agency (Tukes)

Jaana Pasanen Finnish Safety and Chemicals Agency (Tukes)

Petteri Taalasniemi Finnish Safety and Chemicals Agency (Tukes)

Elina Väänänen Finnish Safety and Chemicals Agency (Tukes)

Pirjo Tuomi Golder Associates Oy

Leena Mannonen Ministry of Agriculture and the Forestry (MMM)

Leila Vilhunen Ministry of Employment and the Economy (TEM)

Pekka Jalkanen Ministry of the Environment (YM)

Marilla Lahtinen Ministry of Social Affairs and Health (STM)

Matti Viluksela National Institute for Health and Welfare (THL)

Katri Talvioja Orion Pharma

Maarit Priha Pöyry Finland Oy

Ulrika Backman Technical Research Centre of Finland (VTT)

Markus Linder Technical Research Centre of Finland (VTT)

Nina Nieminen Technology Centre KETEK Ltd

Jussi Kukkonen University of Eastern Finland (ISY)

Nina Honkela University of Helsinki

Arho Toikka University of Helsinki

Annika Adamsson University of Turku


Island Sigurbjörg Gísladóttir Environment Agency of Iceland (UST)

Norway Sjur Andersen Climate and Pollution Agency (KLIF)

Marius Gudbransen Climate and Pollution Agency (KLIF)

Erik Joner Norwegian Institute for Agricultural and Environmental Research (Bioforsk)

Lise Marie Fjellsbø Norwegian Institute for Air Research (NILU)

Marit Låg Norwegian Institute of Public Health (FHI)

Ailbhe Macken Norwegian Institute for Water Research, Ecotoxicology and Risk Assessment (NIVA)

Deborah Oughton Norwegian University of Life Sciences (UMB)

Sweden

Kettil Svensson National Food Agency (SLV)

Alicja Andersson Swedish Chemicals Agency (Kemi)

Yvonne Andersson Swedish Chemicals Agency (Kemi)

Åsa Bringmyr Swedish Chemicals Agency (Kemi)

Celia Fischer Swedish Chemicals Agency (Kemi)

Edda Hahlbeck Swedish Chemicals Agency (Kemi)

Lena Hellmér Swedish Chemicals Agency (Kemi)

Ivar Lundbergh Swedish Chemicals Agency (Kemi)

Katarzyna Malkiewiz Swedish Chemicals Agency (Kemi)

Ing-Marie Olsson Swedish Chemicals Agency (Kemi)

Brita Oredsson Hagström Swedish Chemicals Agency (Kemi)

Emma Vikstad Swedish Chemicals Agency (Kemi)

Maria Wallén Swedish Chemicals Agency (Kemi)

Geert Cornelis University of Gothenburg

Other

Clarisse Durand (by teleconference) Ministry of Ecology, Sustainable Development, Transports and Housing, France

Henrik Laursen DG Environment, European Commission (EC)

Marita Luotamo European Chemicals Agency (ECHA)

Peter Kearns Environment, Health and Safety Programme, OECD (OECD EHS/ENV)

Juan Piñeros Garcet Federal public service for health, food chain safety and the environment, Belgium

Kaja Kasemets National Institute of Chemical Physics and Biophysics (KBFI), Estonia

Nicole Palmen National Institute for Public Health and the Environment (RIVM), The Netherlands

Regulatory Safety Assessment of NanomaterialsAre we facing the same challenges as the regulation of endocrine disrupting chemicals?

Ved Stranden 18DK-1061 København Kwww.norden.org

The Nordic NanoNet Workshop and EDC discussion was organised in October 2011 in Espoo, Finland as part of the 2011 Finnish chairmanship of the Nordic Council of Ministers (NMR). The workshop focused on the safety assessment and management of nanomaterials (NMs) while reflecting on experiences in regulating endocrine disrupting chemicals (EDCs). This report describes the presentations, break-out group discussions and conclusions of the meeting. The regulatory frameworks and links between NMs and EDCs as well as the applicability of test guidelines and risk assessment tools for nanomaterials were addressed in presen-tations and break-out group work. Regulatory possibilities were further considered in a panel-led discussion. The Nordic dimen-sion was of special interest: strengthening of Nordic regulatory cooperation in the field of nanosafety gained support, while com-mencing a TG/GD project in the OECD test guideline programme was seen a concrete idea for future cooperation.

Regulatory Safety Assessment of Nanomaterials

TemaN

ord 2012:515

TemaNord 2012:515ISBN978-92-893-2343-7http://dx.doi.org/10.6027/TN2012-515

conference proceeding

TN2012515 omslag.indd 1 15-06-2012 09:59:32

http://www.norden.org

http://dx.doi.org/10.6027/TN2012-515